CN105209445B - The method for treating dyskinesia and associated conditions - Google Patents

The method for treating dyskinesia and associated conditions Download PDF

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CN105209445B
CN105209445B CN201480026483.0A CN201480026483A CN105209445B CN 105209445 B CN105209445 B CN 105209445B CN 201480026483 A CN201480026483 A CN 201480026483A CN 105209445 B CN105209445 B CN 105209445B
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alkyl
compound
amino
formulas
dyskinesia
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CN105209445A (en
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约翰·恰莱拉
约翰·格鲁纳
安德鲁·G·雷奥姆
迈克尔·S·萨波里托
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Melli Orr pharmaceutical II limited liability company
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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    • A61K31/4245—Oxadiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P25/20—Hypnotics; Sedatives
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Composition the present disclosure describes the compound in the method available for treatment dyskinesia or associated conditions and its pharmaceutically acceptable salt and comprising it and preparation and the method for treating dyskinesia or associated conditions.The present disclosure describes available for treating and/or prevent dyskinesia or the compound of other illnesss, composition and comprising treating or preventing the compound of activity or the preparation of its pharmaceutically acceptable salt and method for treating dyskinesia or other illnesss.

Description

The method for treating dyskinesia and associated conditions
Technical field
The present disclosure describes the compound for treating and/or preventing dyskinesia or other illnesss, include treatment or pre- The composition and preparation of anti-active compound or its pharmaceutically acceptable salt and for treating dyskinesia or other diseases The method of disease.
Background of invention
Mesocarb (Sydnocarb) (that is, 3- (beta-phenyl isopropyl)-N- phenylcarbamoyl sydnone imines (sydnonimine) mesocarb (mesocarb)) is also referred to as, is a kind of ideomotor movement stimulant.In Russia, double benzene this Ketoamine has used more than 30 years, for treating various neuropsychiatric comorbidity diseases, such as weak, apathy and adynamia (Anokhina et al., Zh Nevropatol Psikhiatr Im S S Korsakova, 1974,74,594-602；Vinar Et al., Neuropsychopharmacology, 1991,5,201-217；And Cody, J.Occup.Environ.Med., 2002, 44,435-450).Although most of is beneficial (anecdotal), evidence can be shown that mesocarb is added in weight Durability during physical exertion and the resistance to environmental stress source such as low temperature, low gravitation and anoxic.Mesocarb can also be There is beneficial (Rudenko etc. in terms for the treatment of alcohol abuse, Attention deficit hyperactivity disorder (ADHD) and cognitive impairment People, Agressologie, 1979,20,265-270；Vinar et al., see above；Cody, see above).
Although the promotion for the transmission to dopamine (DA) mediation that mesocarb induces is filled in microdialysis research Divide and determine, but do not known for the definite property of this effect (that is, DA releases suppress relative to DA transporters (DAT)) (Gainetdinov et al., Eur.J.Pharmacol., 1997,340,53-58；Afanas'ev et al., Pharmacol.Biochem.Behav.,2001,69,653-658；Anderzhanova et al., Eur.J.Pharmacol., 2001,428,87-95).Recently, having proven to mesocarb has DAT activity and does not cause the chemical combination of dopamine D_2 receptors Least hypnosia (Gruner et al., J.Pharmacol.Exp.Therap., 2011,337,380-390) specific to thing. Based in synaptosomes in rat brain in vivo Experimental report mesocarb weaken norepinephrine reuptake (Et al., Pol.J.Pharmacol.Pharm.,1981,33,141-147).It is non-that mesocarb is also metabolized as D- peaces in humans and animals He is bright (D-ampheatmine) (D-AMPH), but the effect for D-AMPH in the net vivo effect of mesocarb is unclear Chu.Pharmacological characteristic is largely overlapping inside mesocarb and D-AMPH, otherwise show mesocarb and D- AMPH functionally undistinguishables, otherwise metabolin D-AMPH significantly causes the effect as caused by mesocarb (Gainetdinov et al., see above；Witkin et al., J.Pharmacol.Exp.Ther.1999,288,1298-1310； Anderzhanova et al., Ann.NY Acad.Sci., 2000,914,137-145；Flood et al., Psychopharmacology,2010,211,325-336).However, some significant differences between both medicines be present.No D-AMPH is same as, (Mashkovskil etc. is not reported for notable toxic insults of the mesocarb in people and abuse potential People, Zh Nevropatol Psikhiatr Im S S Korsakova, 1971,71,1704-1709；Rudenko et al., see Above).Compared to D-AMPH, the stimulating effect of mesocarb more progressively produces, lasting longer, and without notable Euphoria, kinesitherapy nerve is excited or periphery sympathomimetic nerve effect, as tachycardia and hypertension (Rudenko et al., see on Text).In animal, compared to D-AMPH, mesocarb produces the slower of extracellular DA in rat striatum and volt core And more progressive increase (Gainetdinov et al., is seen above；Witkin et al., see above；Anderzhanova et al., see on Text).Relative to D-AMPH, the mesocarb of equimolar dosage produces less quick movement and stereotypy and neurotoxicity The smaller change of label (such as DA losses, the generation of reactive oxygen species or the increase of lipid peroxidation specific indexes) (Gainetdinov et al., see above；Witkin et al., see above；Anderzhanova et al., see above；Afanas'ev etc. People, see above；Bashkatova et al., Ann.NY Acad.Sci., 2002,965,180-192).In addition, mesocarb is not Displaying is for the least hypnosia caused by the dopamine D_2 receptors characteristic related to D-AMPH seen by D-AMPH (Gruner et al., seeing above).It is intended to study effect of the DAT inhibitor in Parkinson's disease (Parkinson's Disease) Some researchs have shown there is considerably less effectiveness or no effectiveness to the disease, especially in DAT inhibitor pair and pa In terms of the potential utility of the related L-3,4 dihydroxyphenylalanine induction property dyskinesia of golden Sen Shi diseases (J., Neuropsych.Dis.Treat.,2010,6,93-97；Hauser et al., Mov.Disord, 2007,22,359-365；With Rascol et al., Arch Neurol., 2008,65,577-583).
Brief summary of the invention
The disclosure covers the dyskinesia available for treatment mammal or compound, composition and the system of other illnesss Agent.In some embodiments, mammal suffers from or under a cloud suffers from dyskinesia or another illness.Specifically, can use Formulas I as described herein is included in compound, composition and the preparation for the treatment of dyskinesia or other illnesss Compound, composition and the preparation of compound.
The disclosure provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2's Compound；
Or its pharmaceutically acceptable salt, wherein：U is C or N；Each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (= O)OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulphur Acyl group, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl or Dialkyl amido Sulfinylalkyl, wherein r are 0,1,2,3,4 or 5；Each R2And R3It independently is H, C1-C6Alkyl, C2-C6 Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-C (=O) OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulfonyl Base, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl, Dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein n are 0,1,2,3 or 4；Each R4And R5Independently For H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, halo Alkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, first Amide groups, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino Asia sulphur Acyl group, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide oxygen Base, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino sulphur Acyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, monoalkyl ammonia Base Sulfinylalkyl, dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein p are 0,1,2,3 or 4；W For H or C1-C6Alkyl；Y is H, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2、-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl Sulfonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, amino sulphur Acyl group, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl Epoxide, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, single alkane Base amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl Or dialkyl amido Sulfinylalkyl；X is O or S；Z is O or S；R7For H or halogen；Q is H, C1-C6Alkyl, aryl, C1-C6 Alkylaryl, C3-C6Cycloalkyl or heteroaryl, it is each optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；R8For H Or C1-C6Alkyl, each R6It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkane sulphur Base ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、-NH (C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H ,-C (=O) C1-C6Alkyl ,-C (=O) C1-C6Alkoxy, alcoxyl carbonyl Base, formamido, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, monoalkyl ammonia Base sulfinyl, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxyl sulphur Acyloxy, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, ammonia Base Sulfonylalkyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, single alkane Base amino Sulfinylalkyl or dialkyl amido Sulfinylalkyl.
The disclosure is also provided comprising Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or formula The composition of Id-2 compound or its pharmaceutically acceptable salt.In some embodiments, composition is also controlled comprising another Agent is treated, another therapeutic agent is the medicament of anti-Parkinson agent, the medicament for treating dyskinesia or induced movement obstacle.
The disclosure also provides the preparation for being applied with tablet, gel cap or capsules per os, and it includes about 1mg to about 1000mg Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 compound or its Pharmaceutically acceptable salt.In some embodiments, preparation is also included selected from anti-Parkinson agent, for treating dyskinesia Another therapeutic agent of the medicament of medicament or induced movement obstacle.
The method that the disclosure also provides the dyskinesia or other illnesss for the treatment of mammal, it is included to there is this needs Mammal applies Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or the Formulas I d-2 of effective dose Compound：
Or its pharmaceutically acceptable salt, wherein：U is C or N；Each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (= O)OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulphur Acyl group, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl or Dialkyl amido Sulfinylalkyl, wherein r are 0,1,2,3,4 or 5；Each R2And R3It independently is H, C1-C6Alkyl, C2-C6 Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-C (=O) OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulfonyl Base, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl, Dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein n are 0,1,2,3 or 4；Each R4And R5Independently For H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, halo Alkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, first Amide groups, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino Asia sulphur Acyl group, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide oxygen Base, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino sulphur Acyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, monoalkyl ammonia Base Sulfinylalkyl, dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein p are 0,1,2,3 or 4；W For H or C1-C6Alkyl；Y is H, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2、-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl Sulfonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, amino sulphur Acyl group, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl Epoxide, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, single alkane Base amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl Or dialkyl amido Sulfinylalkyl；X is O or S；Z is O or S；R7For H or halogen；Q is H, C1-C6Alkyl, aryl, C1-C6 Alkylaryl, C3-C6Cycloalkyl or heteroaryl, it is each optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；R8For H Or C1-C6Alkyl；And each R6It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkane Sulfenyl ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、- NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H ,-C (=O) C1-C6Alkyl ,-C (=O) C1-C6Alkoxy, alcoxyl carbonyl Base, formamido, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, monoalkyl ammonia Base sulfinyl, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxyl sulphur Acyloxy, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, ammonia Base Sulfonylalkyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, single alkane Base amino Sulfinylalkyl or dialkyl amido Sulfinylalkyl；Or its pharmaceutically acceptable salt, wherein other illnesss It is restless leg syndrome (such as drug-induced property or idiopathic), drug-induced property dystonia, chorea (such as Huntington's disease (Huntington's disease), toxin induce property chorea, Sydenham's chorea (Sydenham's chorea), Chorea gravidarum, Wilson's disease (Wilson's disease), drug-induced property chorea and metabolic and endocrine phase Close property chorea), twitch (such as the twitch of motor tic, voice, simple tics, complexity twitch and gilles de la Tourette's syndrome (Tourette syndrome)), dystonia (such as acute dystonic, generalized dystonia, Focal dystonias, section Section property dystonia, property dystonia, osculant dystonia, psychogenic dystonia and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped movement disorder (such as related to autism dyskinesia, hereditary motor obstacle With childhood dyskinesia), compulsive disorder, narcolepsy (such as dampinging off), propagated spongiform encephalopathy (such as Ke-refined Er Shi Sick (Creutzfeldt-Jakob disease) and kuru (Kuru)), Neuroacanthocytosis, epileptic attack and shy Faint, athetosis (such as athetosis related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy) or brain fiber crops Numbness.
In some embodiments, dyskinesia be levodopa dyskinesia, chronic or tardive barrier Hinder or orofacial dyskinesia.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt, it is used to treating dyskinesia (such as levodopa dyskinesia, chronic Or tardive dyskinesia and orofacial dyskinesia), restless leg syndrome (such as drug-induced property or idiopathic), drug-induced property Dystonia, chorea (such as Huntington's disease, toxin induction property chorea, Sydenham's chorea, chorea gravidarum, prestige Your Xun Shi is sick, drug-induced property chorea and metabolic and endocrine correlation chorea), twitch (such as motor tic, language Sound twitch, simple tics, complexity twitch and gilles de la Tourette's syndrome), dystonia (such as acute dystonic, systemic Dystonia, Focal dystonias, segmental dystonias, property dystonia, osculant dystonia, psychogenic tension force barrier Hinder and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped movement disorder (fortune such as related to autism Dynamic obstacle, hereditary motor obstacle and childhood dyskinesia), compulsive disorder, narcolepsy (such as dampinging off), propagated sea Continuous shape encephalopathic (such as Creutzfeldt-Jakob disease and kuru), Neuroacanthocytosis, epileptic attack and convulsions, athetosis (such as athetosis related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy) or cerebral paralysis.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt, it is used to manufacture treating the medicament of following disease：Dyskinesia is (such as left-handed DOPA induce property dyskinesia, chronic or tardive dyskinesia and orofacial dyskinesia), (such as medicine lures restless leg syndrome Hair property or idiopathic), drug-induced property dystonia, chorea (such as Huntington's disease, toxin induce property chorea, Xi Dengha Mu Shi choreas, chorea gravidarum, Wilson's disease, drug-induced property chorea and metabolic and endocrine correlation dancing Disease), twitch (such as the twitch of motor tic, voice, simple tics, complexity twitch and gilles de la Tourette's syndrome), tension force hinder Hinder (such as acute dystonic, generalized dystonia, Focal dystonias, segmental dystonias, property dystonia, in Between type dystonia, psychogenic dystonia and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped fortune Dynamic obstacle (such as related to autism dyskinesia, hereditary motor obstacle and childhood dyskinesia), compulsive disorder, hair As property sleep disease (such as dampinging off), propagated spongiform encephalopathy (such as Creutzfeldt-Jakob disease and kuru), Neuroacanthocytosis, Epileptic attack and convulsions, athetosis (such as athetoid related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy Disease) or cerebral paralysis.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt, it is used to treating dyskinesia (such as levodopa dyskinesia, chronic Or tardive dyskinesia and orofacial dyskinesia), restless leg syndrome (such as drug-induced property or idiopathic), drug-induced property Dystonia, chorea (such as Huntington's disease, toxin induction property chorea, Sydenham's chorea, chorea gravidarum, prestige Your Xun Shi is sick, drug-induced property chorea and metabolic and endocrine correlation chorea), twitch (such as motor tic, language Sound twitch, simple tics, complexity twitch and gilles de la Tourette's syndrome), dystonia (such as acute dystonic, systemic Dystonia, Focal dystonias, segmental dystonias, property dystonia, osculant dystonia, psychogenic tension force barrier Hinder and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped movement disorder (fortune such as related to autism Dynamic obstacle, hereditary motor obstacle and childhood dyskinesia), compulsive disorder, narcolepsy (such as dampinging off), propagated sea Continuous shape encephalopathic (such as Creutzfeldt-Jakob disease and kuru), Neuroacanthocytosis, epileptic attack and convulsions, athetosis (such as athetosis related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy) or cerebral paralysis.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt, it is used to manufacture treating the medicament of following disease：Dyskinesia is (such as left-handed DOPA induce property dyskinesia, chronic or tardive dyskinesia and orofacial dyskinesia), (such as medicine lures restless leg syndrome Hair property or idiopathic), drug-induced property dystonia, chorea (such as Huntington's disease, toxin induce property chorea, Xi Dengha Mu Shi choreas, chorea gravidarum, Wilson's disease, drug-induced property chorea and metabolic and endocrine correlation dancing Disease), twitch (such as the twitch of motor tic, voice, simple tics, complexity twitch and gilles de la Tourette's syndrome), tension force hinder Hinder (such as acute dystonic, generalized dystonia, Focal dystonias, segmental dystonias, property dystonia, in Between type dystonia, psychogenic dystonia and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped fortune Dynamic obstacle (such as related to autism dyskinesia, hereditary motor obstacle and childhood dyskinesia), compulsive disorder, hair As property sleep disease (such as dampinging off), propagated spongiform encephalopathy (such as Creutzfeldt-Jakob disease and kuru), Neuroacanthocytosis, Epileptic attack and convulsions, athetosis (such as athetoid related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy Disease) or cerebral paralysis.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt or include its composition, it is used to treat the sleep for being characterised by being interrupted The sleep-disorder of timetable, and for treating Parkinson's disease.
The disclosure also provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Compound or its pharmaceutically acceptable salt or include its composition, it is used to manufacture is characterised by by treat The sleep-disorder of disconnected length of one's sleep table and to treat the medicament of Parkinson's disease.
Brief description
Figure 1A and 1B show the Sprague-Dawley rats of 6-OHDA unilateral lesions are carried out respectively L-3,4 dihydroxyphenylalanine apply and The result that mesocarb is applied.
Fig. 2 shows that the L- for the rat that mesocarb rather than Te Suofenxin (Tesofensine) improve 6-OHDA processing is more Bar induce property dyskinesia.
The effect for the effect of Fig. 3 shows mesocarb to L-3,4 dihydroxyphenylalanine to motor function.
Fig. 4 shows the result for spacious field (open field) the activity measure for wherein assessing motion and sensorimotor parameter.
When Fig. 5 is shown in progress eeg analysis to monitor brain and muscle activity, mesocarb is compared to medium Control dose-dependently increases wakeup time.
Fig. 6 show assessed by the grade of abnormal limbs, oral area and the facial movement of evaluating single animal it is independent Or the effect of the long-term L-3,4 dihydroxyphenylalanine combined with mesocarb.
Fig. 7 shows the PK curves of pharmaceutical preparation, and it shows to produce slightly higher blood in several time points based on the preparation of ethanol Pulp-water is put down.
Fig. 8 is shown via the L-3,4 dihydroxyphenylalanine induction property dyskinesia for orally giving mesocarb in the 6-OHDA rats handled The evaluation of the effect of middle.
Fig. 9 is shown in using having a mesocarb and L-3,4 dihydroxyphenylalanine without mesocarb handles the unilateral lesions of 2 weeks In the forelimb step number regulation test (forelimb adjusting step test) of 6-OHDA rats, mesocarb is to motion The effect of function.
Figure 10 is shown in the forelimb step number regulation test of the 6-OHDA rats of the unilateral lesions handled using L-3,4 dihydroxyphenylalanine, mouth Clothes give effect of the mesocarb to motor function.
Figure 11 is shown in the not 6-OHDA rats of the unilateral lesions using L-3,4 dihydroxyphenylalanine processing, and mesocarb is not to extremely Voluntomotory effect.
Embodiment
Unless the context clearly indicates otherwise, otherwise term " one (a) " as used herein or " one (an) " mean " at least One " or " one or more in one ".
Term " about " as used herein means numerical approximation and small change will not significantly affect disclosed in The implementation of embodiment.When using numerical limitation, unless the context indicates otherwise, otherwise " about " mean that numerical value can be with ± 10% Change and be maintained in the range of disclosed embodiment.
Term " alkenyl " as used herein means the monovalent non-branched or side chain wherein with one or more double bonds Hydrocarbon chain.The double bond of alkenyl can not be conjugated or be conjugated with another unsaturated group.Suitable alkenyl includes but is not limited to (C2-C6) alkene Base, such as vinyl, pi-allyl, cyclobutenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2- ethyl hexenes Base, 2- propyl group -2- cyclobutenyls, 4- (2- methyl -3- butylene)-pentenyl.Alkenyl can be unsubstituted or suitable by one or two Substituent substitution.
Term " alkoxy " as used herein means-O- alkyl, wherein alkyl as defined herein.Alkoxy can not by Substitution is substituted by one or two suitable substituent.In some embodiments, the length of the alkyl chain of alkoxy be 1 to 6 carbon atoms, such as herein referred to as " (C1-C6) alkoxy ".
Term " alkyloxysulfonyl " as used herein means-S (=O)2O- moieties, wherein alkyl such as this paper institutes Definition.
Term " alkoxy sulfonyloxy " as used herein means-OS (=O)2O- moieties, wherein alkyl are as originally Text is defined.
Term " alkyl (alkyl) " or " alkyl (alkyl group) " as used herein mean the monovalent non-branch of saturation Chain or side chain hydrocarbon chain.The example of alkyl includes but is not limited to (C1-C6) alkyl, as methyl, ethyl, propyl group, isopropyl, 2- methyl- 1- propyl group, 2- methyl-2-propyls, 2-methyl-1-butene base, 3- methyl isophthalic acids-butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- Propyl group, 2- methyl-1-pentenes base, 3- methyl-1-pentenes base, 4- methyl-1-pentenes base, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- Methyl -2- amyl groups, 2,2- dimethyl -1- butyl, 3,3- dimethyl -1- butyl, 2- ethyl -1- butyl, butyl, isobutyl group, uncle Butyl, amyl group, isopentyl, neopentyl and hexyl, and longer alkyl, such as heptyl and octyl group.Alkyl can it is unsubstituted or by One or two suitable substituent substitution.
Term " alkyl sulphonyl " as used herein means-S (=O)2- moieties, wherein alkyl as determined herein Justice.
Term " Alkylsulfonylalkyl " as used herein means-alkyl-S (=O)2- moieties, wherein alkyl (each case) as defined herein.
Term " alkyl sulfonyl-amino " as used herein means-NHS (=O)2- moieties, wherein alkyl are as originally Text is defined.
Term " alkylsulfonyloxy " as used herein means-OS (=O)2- moieties, wherein alkyl such as this paper institutes Definition.
Term " alkynyl " as used herein means the monovalent non-branched or side chain wherein with one or more three keys Hydrocarbon chain.Three keys of alkynyl can not be conjugated or be conjugated with another unsaturated group.Suitable alkynyl includes but is not limited to (C2-C6) alkynes Base, such as acetenyl, propinyl, butynyl, pentynyl, hexin base, methylpropynyl, 4- methyl isophthalic acids-butynyl, 4- propyl group -2- Pentynyl and 4- butyl -2- hexin bases.Alkynyl can be unsubstituted or substituted by one or two suitable substituent.
Term " amino sulfinyl " as used herein means-S (=O) NH2Part.
Term " amino Sulfinylalkyl " as used herein means-alkyl-S (=O) NH2Part, wherein alkyl are such as It is defined herein.
Term " amino-sulfonyl " as used herein means-S (=O)2NH2Part.
Term " amino-sulfonyl alkyl " as used herein means-alkyl-S (=O)2-NH2Part, wherein alkyl are as originally Text is defined.
What term " aralkyl " as used herein meant to be combined with aryl and alkyl as defined above has 6 to 20 The part of individual carbon atom.Any aralkyl moiety of compound as described herein is optionally carried herein by one or more The substituent substitution arrived.
Term " aryl " as used herein means monocyclic or polycyclic-aromatic group comprising carbon and hydrogen atom.Suitably The example of aryl includes but is not limited to phenyl, tolyl, anthryl, fluorenyl, indenyl, azulene base and naphthyl, and benzo-fused Isocyclic part, such as 5,6,7,8- tetralyls.Aryl can be unsubstituted or substituted by one or two suitable substituent. In some embodiments, aryl is monocyclic, and its middle ring includes 6 carbon atoms, herein referred to as " (C6) aryl ".
What term " aralkyl " as used herein meant to be combined with aryl and alkyl as defined above has 6 to 20 The part of individual carbon atom.Any aralkyl moiety of compound as described herein is optionally carried herein by one or more The substituent substitution arrived.
Term " aryloxy group " as used herein means-O- aryl, wherein aryl as defined herein.Aryloxy group can not by Substitution is substituted by one or two suitable substituent.In some embodiments, the aryl rings of aryloxy group are monocyclic, wherein Ring includes 6 carbon atoms, herein referred to as " (C6) aryloxy group ".
Term " benzyl " as used herein means-CH2- phenyl.
Term " alkoxy carbonyl group " as used herein means-C (=O), and O- moieties, wherein alkyl are as defined herein.
Term " carbonyl " as used herein be formula-C (O)-divalent group.
Term " formamido " as used herein means-C (=O) O-NR'R " parts, and wherein R' and R are " independently of one another H, alkyl, aryl or aralkyl are represented, all as defined herein.
Term " compound as described herein " as used herein jointly means that compound of formula I is pharmaceutically acceptable with its Salt.Compound differentiates herein by their chemical constitution and/or chemical name.When compound passes through chemical constitution During with both chemical names to refer to, and when chemical constitution and chemical name conflict, chemical constitution determines the body of compound Part.Compound can contain one or more chiral centres and/or double bond, and therefore be used as stereoisomer such as double bond isomer (that is, geometric isomer), enantiomter or diastereoisomer are present.Chemical constitution depicted herein and therefore this paper institutes The compound stated covers the enantiomter and stereoisomer of all respective compounds, i.e. the pure form (example of stereoisomer Such as, geometry is pure, enantiomeric pure or diastereisomericallypure pure) and both enantiomter and stereoisomer mixture. Enantiomter and stereoisomer mixture can be split as to their component enantiomers or solid by well-known process Isomers, method such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatogram, make compound crystallization for chiral salt complex or make Compound crystallizes in chiral solvent.Can also be by well known dissymmetric synthesis, from stereoisomer or enantiomeric pure Intermediate, reagent or catalyst, obtain enantiomter and stereoisomer.
As used herein term " include (comprising) " (and comprising any form, as " comprise ", " comprises " and " comprised "), " with (having) " (and with any form, such as " have " and " has "), " including (including) " (and including any form, such as " includes " and " include ") or " contain (containing) " (and any form contained, such as " contains " and " contain ") is including or open, and It is not excluded for key element that is extra, not addressing or method and step.
Term " dialkyl amino sulfonyl " as used herein means-S (=O) NR'R " parts, and wherein R' and R " are respective H, alkyl, aryl or aralkyl are independently represented, all as defined herein.
Term " dialkyl amido Sulfinylalkyl " as used herein means-alkyl-S (=O) NR'R " parts, its As defined herein, and R' and R " represent H, alkyl, aryl or aralkyl to middle alkyl independently of one another, all as determined herein Justice.
Term " dialkyl amino sulfonyl " as used herein means-S (=O)2NR'R " parts, wherein R' and R " are each From H, alkyl, aryl or aralkyl is independently represented, all as defined herein.
Term " dialkyl amino sulfonyl alkyl " as used herein means-alkyl-S (=O)2- NR'R " parts, its As defined herein, and R' and R " represent H, alkyl, aryl or aralkyl to middle alkyl independently of one another, all as determined herein Justice.
Term " halogen " and " halogen " as used herein mean fluorine, chlorine, bromine and/or iodine.
Term " heteroaryl " as used herein means comprising carbon atom, hydrogen atom and independently selected from nitrogen, oxygen and sulphur One or more hetero atoms (suitably 1 to 3 hetero atom) monocyclic-or polycyclic aromatic ring.The illustrative example of heteroaryl Including but not limited to pyridine radicals, pyridazinyl, pyrimidine radicals (pyrimidyl), pyrazolyl (pyrazyl), triazine radical, pyrrole radicals, pyrrole Oxazolyl (pyrazolyl), imidazole radicals, (1,2,3)-triazolyl and (l, 2,4)-triazolyl, pyrazinyl (1,2- pyrazinyls and 1,4- Pyrazinyl), pyrimidine radicals (pyrimidinyl), tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, furyl, thiophene (phienyl), isoxazolyls are He oxazolyl for base.Heteroaryl can be unsubstituted or substituted by one or two suitable substituent. In some embodiments, heteroaryl is monocyclic that its middle ring includes 2 to 5 carbon atoms and 1 to 3 hetero atom, herein quilt Referred to as " (C2-C5) heteroaryl ".
Term " Heterocyclylalkyl " as used herein means comprising carbon atom and hydrogen atom and selected from nitrogen, oxygen and sulphur extremely Lack a hetero atom (suitably 1 to 3 hetero atom) and without undersaturated monocyclic or polycyclic.The example of Heterocyclylalkyl is included but not It is limited to pyrrolidinyl, pyrrolidino, piperidyl, piperidino, piperazinyl, Piperazino, morpholinyl, morpholino, thio Quinoline base, thiomorpholine generation and pyranose.Heterocyclylalkyl can be unsubstituted or substituted by one or two suitable substituent.One In a little embodiments, Heterocyclylalkyl is monocyclic or two rings or monocyclic, and its middle ring includes 3 to 6 carbon atoms and 1 to 3 miscellaneous original Son, herein referred to as (C1-C6) Heterocyclylalkyl.
Term " heterocyclic group " or " heterocycle " as used herein mean Heterocyclylalkyl or heteroaryl.
Term " alkyl " as used herein means to be selected from (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl list Valency group, it is optionally substituted by one or two suitable substituent.In some embodiments, the length of the hydrocarbon chain of alkyl It is 1 to 6 carbon atom, herein referred to as " (C1-C6) alkyl ".
Term " hydroxysufonyl " as used herein means-S (=O)2OH parts.
Term " hydroxysulfonamide epoxide " as used herein means-OS (=O)2OH parts.
Phrase " having this needs " as used herein means that animal or mammal have been identified as to ad hoc approach or controlled Treat in need.In some embodiments, can be differentiated by any diagnostic means.In any method as described herein and control In treatment, animal or mammal can have this needs.
Term " separation " as used herein means compound as described herein and other groups such as by routine techniques Separation, other components come from (a) natural origin, as plant or cell, such as bacterial cultures, or (b) synthetic organic chemistry are anti- Answer mixture.
When being applied to mammal and (using or administer to the human for Clinical practice for animal doctor for example, being applied to animal), this Compound described in text can be applied in a separate form.As used herein, " separation " means compound and other components point From other components come from (a) natural origin, as plant or cell, such as bacterial cultures, or the reaction of (b) synthetic organic chemistry are mixed Compound, such as via routine techniques, compound is purified." purifying " means that when disengaged, isolate contains as used herein In terms of the weight of isolate at least 90% or at least 95% or at least 98% or at least 99% compound.
Term " alkyl monosubstituted amino sulfinyl " as used herein means-S (=O) NHR' parts, and wherein R' is H, alkane Base, aryl or aralkyl, all as defined herein.
Term " alkyl monosubstituted amino Sulfinylalkyl " as used herein means-alkyl-S (=O) NHR' parts, wherein As defined herein, and R' is H, alkyl, aryl or aralkyl to alkyl, all as defined herein.
Term " monoalkylaminosulfonyl " as used herein means-S (=O)2NHR' parts, wherein R' are H, alkane Base, aryl or aralkyl, all as defined herein.
Term " monoalkylaminosulfonyl alkyl " as used herein means-alkyl-S (=O)2- NHR' parts, Wherein as defined herein, and R' is H, alkyl, aryl or aralkyl to alkyl, all as defined herein.
Term " pharmaceutically acceptable " as used herein means what is ratified by federal government or management organization of state government Or that lists in American Pharmacopeia or other pharmacopeia being widely recognized as is used for animal (more specifically people).
Phrase " pharmaceutically acceptable salt " as used herein includes but is not limited to may be present in in this composition Compound in acidic-group or basic group salt.It is in nature the compound energy of alkalescence to be contained in this composition It is enough to form a variety of salt with various inorganic acids and organic acid.Add available for the pharmaceutically acceptable acid for preparing such alkali compounds Acid into salt is those to form non-toxic acid addition salts, and non-toxic acid addition salts are containing pharmacologically acceptable anion Salt, including but not limited to sulfate, citrate, maleate, acetate, oxalates, hydrochloride, hydrobromate, hydroiodic acid Salt, nitrate, sulfate, disulfate, phosphate, acid phosphate, isonicotinic acid salt, acetate, lactate, malonate, Mandelate, salicylate, citrate, acid citrate, tartrate, oleate, phthalate, tannate, Pantothenate, biatrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, Portugal Glycuronate, saccharate, formates, benzoate, glutamate, mesylate, esilate, benzene sulfonate, naphthalene sulfonic acids Salt, tosilate and embonate (i.e. 1,1'- methylene-bis--(2- hydroxyl -3- naphthoates)).It is contained in this group The compound comprising amino part in compound can also form pharmaceutically acceptable in addition to above-mentioned acid with various amino acid Salt.The example that may act as the organic amine of salt includes but is not limited to ammonium, trimethyl ammonium, diethyl ammonium and three-(methylol) ammonium methyls. It is contained in can be formed in nature for acid compound with various pharmacologically acceptable cations in this composition Alkali salt.The example of such salt includes alkali metal salt or alkali salt, particularly calcium salt, magnesium salts, sodium salt, lithium salts, zinc salt, ammonium Salt, sylvite and molysite.Another useful salt is L-3,4 dihydroxyphenylalanine salt.
Term " phenyl " as used herein means-C6H5.Phenyl can be unsubstituted or by one or two suitable substitution Base substitutes.
Term " prevention (prevention) " as used herein or " prevention (prevent) ", which mean to reduce, obtains specific disease The risk of disease or illness.It need not mean being completely eliminated for disease or illness.
Term " prodrug " as used herein means the derivative of known directly drugs with function, and the derivative is compared to medicine Delivery characteristics and therapeutic value with enhancing, and active medicine is converted into by enzymatic or chemical process.
Term " purifying " as used herein means that when disengaged isolate contains in terms of the weight of isolate at least 90%th, at least 95%, at least 98% or at least 99% compound as described herein.
" suitable substituent " means not make compound as described herein or for preparing in them as used herein The invalid group of the synthesis effectiveness or pharmacy effectiveness of mesosome.The example of suitable substituent includes but is not limited to：(C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C6) aryl, (C3-C5) heteroaryl, (C3-C7) cycloalkyl, (C1-C8) alkoxy, (C6) virtue Epoxide ,-CN ,-OH, oxo base, halogen ,-NO2、-CO2H、-NH2、-N((C1-C8) alkyl) ,-N ((C1-C8) alkyl)2、-NH ((C6) aryl) ,-N ((C6) aryl)2、-CHO、-CO((C1-C8) alkyl) ,-CO ((C6) aryl) ,-CO2((C1-C8) alkyl) ,- CO2((C6) aryl), alkoxy carbonyl group, formamido, alkyl sulphonyl, amino sulfinyl, alkylsulfonyloxy, dialkyl amino Base sulfinyl, alkyl monosubstituted amino sulfinyl, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkane Base sulfuryl amino, hydroxysulfonamide epoxide, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkoxy sulphonyl Base, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, ammonia Base Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl and dialkyl amido Sulfinylalkyl.Those skilled in the art Stability and pharmacological activity and synthesizing activity that can be based on compound as described herein be readily selected suitable substituent.
" therapeutically effective amount " of phrase as used herein composition as described herein passes through compound as described herein Validity is treated to measure, at least one detrimental effect of wherein illness is improved or mitigated.In one embodiment, it is short " therapeutically effective amount " of language composition as described herein passes through compounds for treating as described herein or the treatment of prevention dyskinesia Validity measures.In some embodiments, effective dose by so as to measure dyskinesia any parameter reduce at least 10%, At least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%.
Term " treatment (treatment) " as used herein or " treatment (treating) " mean disease or illness or Its at least one improvement for distinguishing symptom.In another embodiment, " treatment (treatment) " or " treatment (treating) improvement of at least one measurable physical parameter that can be not necessarily distinguished by patient " is referred to.Further implementing In scheme, " treatment (treatment) " or " treatment (treating) " means on body (such as the stabilization of recognizable symptom Change), in physiologically (such as stabilisation of physical parameter) or both suppressed on body or physiologically entering for disease or illness Exhibition.In still another embodiment, " treatment (treatment) " or " treatment (treating) " refers to the hair for postponing disease or illness Make.
In each place of this specification, the substituent of compound group or can be disclosed with scope.Clearly it is intended to this Scope or group include each independent sub-portfolio of the member of such group and scope.For example, term " C1-6Alkyl " is clearly intended to list Solely open methyl, ethyl, propyl group, C4Alkyl, C5Alkyl and C6Alkyl.
For wherein occurrences exceed compound once, each variable can be selected from the horse for defining the variable The different piece in assorted group of storehouse (Markush group).For example, when description is with two R being present in same compound simultaneously During the structure of group, two R groups can represent to be selected from the different piece for marlcush group defined in R.In another example, When optionally multiple substituents are with for exampleForm when being named, it should be appreciated that substituent " R " can occur on ring " s " number, and " R " can be different piece at each occurrence.In addition, in the above example, when variable T is defined as wrapping When hydrogeneous, such as when T is CH, N, any H can be substituted base replacement.
It should also be clear that some features of the disclosure described for clarity and under the background of independent embodiment also may be used There is provided with single combination of embodiment.On the contrary, the disclosure described for brevity and under the background of single embodiment Various features can also provide individually or with any suitable sub-portfolio.
It should be understood that in where applicable, the disclosure cover the stereoisomer of compound as described herein, diastereoisomer and Optical stereo isomers and its mixture and its purposes.In addition, it should be understood that the stereoisomer of compound as described herein, Diastereoisomer and optical stereo isomers and its mixture are in the scope of the present disclosure.As non-limiting examples, mix Compound can be racemate, or mixture can be comprising relative to a kind of another particular stereoisomer for inequality proportion. In addition, compound can be as substantially pure stereoisomer, diastereoisomer and optical stereo isomers (such as epimerism Body) provide.
Can be that asymmetric (for example, having one or more stereocenters) comes with regard to any compound as described herein Say, unless otherwise directed, otherwise all such stereoisomers (such as enantiomter and diastereoisomer) be intended to including In the scope of the present disclosure.The compound of carbon atom containing Asymmetrical substitute can be separated with optical forms or racemic form. The method that optical forms are prepared from optically-active parent material is known in the art, and such as by resolving racemic mixtures or passes through solid Selectivity synthesis.Many geometric isomers of alkene, C=N double bonds etc. also are present in compound as described herein, and institute There is such desmotrope to be covered by the disclosure.The cis and trans geometric isomer of compound is also included within the disclosure In the range of, and can be separated as isomer mixture or as the isomeric forms of separation.When can have alloisomerism Property or the compound of geometric isomerism when being named with its structure or title without reference to specific R/S or cis/trans configuration, meaning Covering all such isomers.
The fractionation of the racemic mixture of compound can be implemented by any of many methods known in the art, Including for example carrying out classification recrystallization using chiral resolution acid, chiral resolution acid is optically-active into salt organic acid.For being classified The suitable resolving agent of recrystallization method includes but is not limited to optically-active acid, such as tartaric acid, acetyl tartaric acid, dibenzoyl base liquor Stone acid, mandelic acid, malic acid, the D-shaped formula and L-shaped formula of lactic acid and various optically-active camphorsulfonic acids such as beta camphor sulfonic acid.Suitable for classification Other resolving agents of method for crystallising include but is not limited to Alpha-Methyl benzylamine (for example, S-shaped formula and R forms or diastereisomericallypure pure Form), 2- phenylqlvcinols, norephedrine, ephedrine, N- methylephedrines, cyclohexylethylamine, 1,2- diaminocyclohexanes etc. The pure form of stereoisomer.The fractionation of racemic mixture can also by filled with optical resolution agent (for example, dinitro benzene first Aminosulfonylphenyl glycine) post on eluted to implement.Suitable eluting solvent composition can by those skilled in the art Lai It is determined that.
For compound as described herein may include tautomeric forms, it is intended that including all such dynamic isomers Form.Tautomeric forms by singly-bound and adjacent double bonds exchange and adjoint proton migrates and produces.Dynamic isomer Form includes prototropic tautomeric body, and it is the isomers protonation state with identical empirical formula and total electrical charge.Matter Son move become dynamic isomer example include but is not limited to keto-enol to, acid amides-imidic acid to, lactams-lactim to, Acid amides-imidic acid is to, enamine-imines pair and ring form, and proton can occupy two of heterocyclic ring system or more in ring form Multiple positions, including but not limited to 1H- and 3H- imidazoles, 1H-, 2H- and 4H-1,2,4- triazoles, 1H- and 2H- iso-indoles and 1H- and 2H- pyrazoles.Tautomeric forms can be at poised state, or spatially be locked as a kind of shape by suitably substituting Formula.
It would be recognized by those skilled in the art that Formulas I a-1, Formulas I a-2, Formulas I b-1 and Formulas I b-2 compound be " inner salt " simultaneously And can exist as depicted.Formulas I a compound is the dynamic isomer of Formulas I b respective compound.Those skilled in the art It will be recognized that dynamic isomer can be used as discrete entities to exist in the solid state, but in the solution, dynamic isomer pair, which can balance, is One or another kind of tautomeric forms or balance are the mixture of two kinds of dynamic isomers, and this exists depending on dynamic isomer Relative thermodynamic stability in associated media.The compound described in the application cover possible tautomeric forms with A kind of and existing form (or diversified forms) when being applied in vivo in the body circulation of mammal.
It will also be appreciated by the skilled artisan that depict can be by external source acid proton for these previously mentioned each formulas The compound of change, protonate production Ic-1, Formulas I c-2, Formulas I d-1 and Formulas I d-2 sour additive compound.In these compounds In each in, positive charge in five-ring heterocycles (Li such as , oxadiazoles) with the anionic from external source acid is negatively charged contends with Ion is relevant.External source acid may be selected from pharmaceutically acceptable sour list, as those described herein.
It will also be appreciated by the skilled artisan that Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, formula Id-1 and Formulas I d-2 compound at atom site " U " place and during when three substituent differences in addition to the heterocycle for being connected to U, Contain chiral centre (as U=C).In the disclosure cited compound cover the racemic forms of these chipal compounds with And the single mapping such as described with Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 Both isomers.
Compound as described herein also includes hydrate and solvate and anhydrous form and nonsolvated forms.
Compound as described herein may also include all of the atom that is present in midbody compound or final compound Isotope.Isotope, which includes those, has same atoms ordinal number but the different atom of mass number.For example, the isotope of hydrogen includes tritium And deuterium.
In some embodiments, compound or its salt is substantially separate.Being partially separated may include that for example enrichment is originally The composition of disclosed compound.Being basically separated may include containing at least about 50 weight %, at least about 60 weight %, at least about 70 Weight %, at least about 80 weight %, at least about 90 weight %, at least about 95 weight %, at least about 97 weight % or at least about 99 The composition of the compound or its salt of the weight % disclosure.Method for separating compound and its salt is this area routine 's.
Although it is suitable in form that disclosed compound is described at its, it is anticipated that can obtain other officials of similar results Can roll into a ball to be integrated into compound.Specifically, thioamides is considered to have very similar property with thioesters.Aromatic ring The distance between can influence the geometrical pattern of compound, and the distance can be changed by merging the aliphatic chain of different length, Aliphatic chain is optionally substituted or can include amino acid, dicarboxylic acids or diamines.The distance between monomer and phase in compound To being orientated also amido link can be substituted by using the substitute with additional atoms to change.Therefore, carbonyl is substituted with dicarbapentaborane to change Become the tendency of the distance between monomer and dicarbonyl unit to take the reciprocal permutation of two carbonyl moieties and change compound Periodically.Pyromellitic dianhydride represents the bonded another alternative of simple acid amides, and it can change the conformation of compound and physical Matter.Modernism (E.Atherton and R.C.Sheppard, Solid the Phase Peptide of solid phase organic chemistry Synthesis A Practical Approach IRL Press Oxford 1989) allow synthetic molecular weight now close to 5, The dispersed compound of 000 dalton.Other substitute modes are equally effective.
Compound as described herein may also include the derivative referred to as prodrug, and derivative can be by modifying as follows It is prepared by the functional group that is present in compound：Which causes trim to be cracked into parent chemical combination with routine operation or in vivo Thing.The example of prodrug includes the compound of the disclosure as described herein, the compound contain be attached to the compound hydroxyl, One or more molecular moieties of amino, sulfydryl or carboxyl, and when being applied to patient, crack in vivo and form trip respectively From hydroxyl, amino, sulfydryl or carboxyl.The alcohol functional group and amine that the example of prodrug includes but is not limited in the compound of the disclosure Acetic ester derivative, carbamate derivatives and the benzoate derivatives of functional group.The preparation and use of prodrug are in T.Higuchi Et al., volume 14 of " Pro-drugs as Novel Delivery Systems, " A.C.S.Symposium Series and Bioreversible Carriers in Drug Design, Edward B.Roche are edited, American Pharmaceutical Association and Pergamon Press, there is discussion in 1987, this two documents pass through reference It is integrally incorporated herein.
Compound as described herein can also be changed and contain the amine functional group that can form N- oxides.Herein for containing Referring to for the compound of amine functional group also includes N- oxides.When compound contains some amine functional groups, one or more than one Individual nitrogen-atoms can be oxidized and form N- oxides.The example of N- oxides includes the N- oxygen of tertiary amine or nitrogenous heterocyclic nitrogen-atoms Compound.N- oxides can handle corresponding amine to be formed by using oxidant such as hydrogen peroxide or peracid (for example, peroxycarboxylic acid) (referring to Advanced Organic Chemistry, Jerry March, the 4th edition, Wiley Interscience).
Structure depicted herein can omit necessary hydrogen atom to complete appropriate chemical valence.Therefore, in certain situation Under, carbon atom or nitrogen-atoms may seem (that is, only to show that the carbon atom of two keys impliedly also will bonding with open chemical valence To two hydrogen atoms；In addition, the nitrogen-atoms with singly-bound described impliedly will also be bonded to two hydrogen atoms).For example, "- N " will be considered "-NH by those skilled in the art2”.Therefore, it is open any knot in wherein chemical valence depicted herein In structure, hydrogen atom is implicit, and is simply omitted for succinct.
Compound as described herein may also include various electriferous states.For example, one of any compound as described herein Or some can be powered.In some cases, any part with amino can be-NH3 +.Accordingly, there exist in herein Each amino in described any compound can independently be-NH2Or-NH3 +。
The disclosure provides Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2's One or more compounds：
Or its pharmaceutically acceptable salt, wherein：U is C or N；Each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (= O)OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulphur Acyl group, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl or Dialkyl amido Sulfinylalkyl, wherein r are 0,1,2,3,4 or 5；Each R2And R3It independently is H, C1-C6Alkyl, C2-C6 Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-C (=O) OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulfonyl Base, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl, Dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein n are 0,1,2,3 or 4；Each R4And R5Independently For H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, halo Alkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl) ,-C (=O) H, alkoxy carbonyl group, first Amide groups, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino Asia sulphur Acyl group, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide oxygen Base, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino sulphur Acyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, monoalkyl ammonia Base Sulfinylalkyl, dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein p are 0,1,2,3 or 4；W For H or C1-C6Alkyl；Y is H, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2、-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl Sulfonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, amino sulphur Acyl group, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl Epoxide, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, single alkane Base amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl Or dialkyl amido Sulfinylalkyl；X is O or S；Z is O or S；R7For H or halogen；O is H, C1-C6Alkyl, aryl, C1-C6 Alkylaryl, C3-C6Cycloalkyl or heteroaryl, it is each optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；R8For H Or C1-C6Alkyl；And each R6It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkane Sulfenyl ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (=O) OH ,-NH2、-CF3、-O-S(O)2OH、-NH (C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H ,-C (=O) C1-C6Alkyl ,-C (=O) C1-C6Alkoxy, alcoxyl carbonyl Base, formamido, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, monoalkyl ammonia Base sulfinyl, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxyl sulphur Acyloxy, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, ammonia Base Sulfonylalkyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, single alkane Base amino Sulfinylalkyl or dialkyl amido Sulfinylalkyl.
In some embodiments, each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,-CN ,- OH, halogen, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, wherein r are 1,2,3,4 or 5.In some embodiments, each R1It independently is H, C1-C6Alkyl, C1-C6Alkoxy ,- CN ,-OH, halogen, haloalkyl ,-C (=O) OH ,-NH2、-CF3Or-C (=O) H, wherein r are 1,2,3,4 or 5.In some realities Apply in scheme, each R1It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,-CN ,-OH, halogen ,-NH2Or-CF3, wherein r is 1st, 2,3,4 or 5.In some embodiments, each R1It independently is H, C1-C3Alkoxy ,-OH, halogen ,-NH2Or-CF3, its Middle r is 1,2,3,4 or 5.In some embodiments, each R1It independently is H, methoxyl group, ethyoxyl, F, Cl, Br ,-NH2Or- CF3, wherein r is 1,2,3,4 or 5.In some embodiments, each R1Independently be F, Cl or Br, wherein r be 1,2,3,4 or 5.In some embodiments, each R1For F, wherein r is 1,2,3,4 or 5.
In some embodiments, each R2And R3It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,- CN ,-OH, halogen, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, wherein n be 1,2,3 or 4.In some embodiments, each R2And R3It independently is H, C1-C3Alkyl, C1-C3Alcoxyl Base ,-CN ,-OH, halogen, haloalkyl ,-N (C1-C3Alkyl)2、-NO2、-NH2Or-CF3, wherein n is 1,2,3 or 4.At some In embodiment, each R2And R3It independently is H, C1-C3Alkyl ,-CN ,-OH, halogen ,-N (C1-C6Alkyl)2、-NH2Or-CF3, Wherein n is 1,2,3 or 4.In some embodiments, each R2And R3It independently is H, C1-C6Alkyl ,-OH ,-N (C1-C6Alkane Base)2Or halogen, wherein n are 1,2 or 3.In some embodiments, each R2And R3H, F, Cl or Br independently are, wherein n is 1 or 2.In some embodiments, each R2And R3H, F, Cl or Br independently are, wherein n is 1.In some embodiments, R2And R3It is that H and n are 1.
In some embodiments, each R4And R5It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,- CN ,-OH, halogen, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, wherein n be 1,2,3 or 4.In some embodiments, each R4And R5It independently is H, C1-C3Alkyl, C1-C3Alcoxyl Base ,-CN ,-OH, halogen, haloalkyl ,-NO2、-NH2Or-CF3, wherein n is 1,2,3 or 4.In some embodiments, each R4And R5It independently is H, C1-C3Alkyl ,-CN ,-OH, halogen ,-NH2Or-CF3, wherein n is 1,2,3 or 4.In some embodiment party In case, each R4And R5It independently is H, C1-C3Alkyl ,-CN or halogen, wherein n are 1,2 or 3.In some embodiments, often Individual R4And R5H, F, Cl or Br independently are, wherein n is 1 or 2.In some embodiments, each R4And R5Independently be H, F, Cl or Br, wherein n are 1.In some embodiments, R4And R5It is that H and n are 1.
In some embodiments, Y H, C1-C6Alkoxy ,-CN ,-OH, halogen, haloalkyl ,-NH2Or-CF3. In some embodiments, Y H, C1-C3Alkoxy ,-CN ,-OH or halogen.In some embodiments, Y H ,-CN ,-OH, F, Cl or Br.In some embodiments, Y H ,-OH, F, Cl or Br.In some embodiments, Y H.
In some embodiments, (CR4R5)P- Y is C1-C6Alkyl.In some embodiments, (CR4R5)P- Y is C1- C3Alkyl.In some embodiments, (CR4R5)p- Y is methyl or ethyl.
In some embodiments, X O.
In some embodiments, Z O.
In some embodiments, Q is selected from following aryl：Anthryl, indanyl, indenyl, naphthyl, phenanthryl, phenyl and Tetralyl；Or selected from following heteroaryl：Acridinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazole Base, benzothiazolyl, carbazyl, furazanyl, imidazole radicals, indazolyl, indolinyl, indolizine base, indyl, 3H- indyls, Isobenzofuran-base, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyls, naphthyridines Ji, oxadiazolyl, oxazolyls, naphthalene are embedding Metadiazine base (perimidinyl), phenanthridinyl, phenanthroline (phenanthrolinyl), phenazinyl, phenothiazinyl, fen Oxazinyl, phthalazinyl, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, 2H- pyrroles Base (pyrrolyl), pyrrole radicals (pyrryl), quinazolyl, 4H- quinolizines base, tetrazole radical, 1,2,4- thiadiazolyl groups, thianthrene group (thianthrenyl), thiazolyl, thienyl, triazine radical, triazolyl and xanthyl；Wherein aryl or heteroaryl optionally by- (R6)tSubstitution, wherein t are 0,1,2,3,4 or 5.In some embodiments, Q is selected from following aryl：Anthryl, naphthyl and benzene Base；Or selected from following heteroaryl：Benzimidazolyl, benzofuranyl, benzoxazolyl, carbazyl, furazanyl, imidazole radicals, Indazolyl, indolinyl, indolizine base, indyl, 3H- indyls, isoindolyl, isoquinolyl, isothiazolyl, isoxazoles Base, naphthyridines Ji, oxadiazolyl, oxazolyls, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole Cough up base, pyrrole radicals, quinazolyl, thienyl, triazine radical and triazolyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, Wherein t is 0,1,2,3,4 or 5.In some embodiments, Q is the aryl selected from naphthyl and phenyl；Or selected from following heteroaryl Base：Benzimidazolyl, benzoxazolyl, imidazole radicals, indazolyl, indolinyl, indyl, isoquinolyl, isoxazolyl, Evil Oxazolyl, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, pyrrole radicals, thienyl and Triazolyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5.In some embodiments In, Q is the aryl selected from naphthyl and phenyl；Or selected from following heteroaryl：Benzimidazolyl, imidazole radicals, indyl, oxazoles Base, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, pyrrole radicals, thienyl and three Oxazolyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5.In some embodiments, Q For phenyl, pyridazinyl, pyridine radicals, pyrimidine radicals or triazolyl, it is each optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 Or 5.
In some embodiments, each R6It independently is H ,-CN, haloalkyl, C1-C6Alkyl, C1-C6Alkoxy ,- OH, halogen ,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、-N(C1-C6Alkyl)2,-C (=O) C1-C6Alkane Base or-C (=O) C1-C6Alkoxy.In some embodiments, each R6It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,- CN ,-OH, halogen, haloalkyl ,-NH2、-CF3,-N (=O)2,-C (=O) OH ,-O-S (=O)2OH、-N(C1-C6Alkyl)2、- C(O)C1-C6Alkyl or-C (=O) C1-C6Alkoxy.In some embodiments, each R6It independently is H, C1-C3Alkyl ,- CN ,-OH, halogen ,-NH2、-CF3、C1-C3Alkoxy ,-N (O)2,-C (=O) OH ,-O-S (=O)2OH、-N(C1-C3Alkyl)2、- C (=O) C1-C3Alkyl or-C (=O) C1-C3Alkoxy.In some embodiments, each R6It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,-OH, halogen ,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、-N(C1-C3Alkyl)2、-C (=O) C1-C3Alkyl or-C (=O) C1-C3Alkoxy.In some embodiments, each R6It independently is H, F, Cl or Br. In some embodiments, each R6It independently is H or F.
In some embodiments, U C.
In some embodiments, W H.
In some embodiments, R7For H.
In some embodiments, R8For H.
In some embodiments, each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,-CN ,- OH, halogen, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, wherein r are 1,2,3,4 or 5；Each R2And R3It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,-CN ,-OH, Halogen, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, Wherein n is 1,2,3 or 4；Each R4And R5It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy ,-CN ,-OH, halogen Base, haloalkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2Or-C (=O) H, its Middle n is 1,2,3 or 4；Y is H, C1-C6Alkoxy ,-CN ,-OH, halogen, haloalkyl ,-NH2Or-CF3；X is O；Z is O；Q is Selected from following aryl：Anthryl, indanyl, indenyl, naphthyl, phenanthryl, phenyl and tetralyl；Or selected from following heteroaryl： Acridinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, carbazyl, furazanyl, Imidazole radicals, indazolyl, indolinyl, indolizine base, indyl, 3H- indyls, isobenzofuran-base, isoindolyl, isoquinolin Base, isothiazolyl, isoxazolyls, naphthyridines Ji, oxadiazolyl, oxazolyls, perimidinyl, phenanthridinyl, phenanthroline, It is phenazinyl, phenothiazinyl, phenoxazine groups, phthalazinyl, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, phonetic Piperidinyl, pyrrole radicals, 2H- pyrrole radicals, pyrrole radicals, quinazolyl, 4H- quinolizines base, tetrazole radical, 1,2,4- thiadiazolyl groups, thianthrene group, Thiazolyl, thienyl, triazine radical, triazolyl and xanthyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, wherein t is 0th, 1,2,3,4 or 5；Each R6It independently is H ,-CN, haloalkyl, C1-C6Alkyl, C1-C6Alkoxy ,-OH, halogen ,-N (= O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、-N(C1-C6Alkyl)2,-C (=O) C1-C6Alkyl or-C (=O) C1- C6Alkoxy；U is C；W is H；R7For H；And R8For H.
In some embodiments, each R1It independently is H, C1-C6Alkyl, C1-C6Alkoxy ,-CN ,-OH, halogen, halogen Substituted alkyl ,-C (=O) OH ,-NH2、-CF3Or-C (=O) H, wherein r are 1,2,3,4 or 5；Each R2And R3It independently is H, C1- C3Alkyl, C1-C3Alkoxy ,-CN ,-OH, halogen, haloalkyl ,-N (C1-C3Alkyl)2、-NO2、-NH2Or-CF3, wherein n is 1st, 2,3 or 4；Each R4And R5It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,-CN ,-OH, halogen, haloalkyl ,-NO2、- NH2Or-CF3, wherein n is 1,2,3 or 4；Y is H, C1-C3Alkoxy ,-CN ,-OH or halogen；X is O；Z is O；Q is selected from anthracene The aryl of base, naphthyl and phenyl；Or selected from following heteroaryl：Benzimidazolyl, benzofuranyl, benzoxazolyl, carbazole Base, furazanyl, imidazole radicals, indazolyl, indolinyl, indolizine base, indyl, 3H- indyls, isoindolyl, isoquinolyl, Isothiazolyl, isoxazolyls, naphthyridines Ji, oxadiazolyl, oxazolyls, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, Pyridine radicals, pyrimidine radicals, pyrrole radicals, pyrrole radicals, quinazolyl, thienyl, triazine radical and triazolyl；Wherein aryl or heteroaryl are appointed Selection of land quilt-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；Each R6It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,- CN ,-OH, halogen, haloalkyl ,-NH2、-CF3,-N (=O)2,-C (=O) OH ,-O-S (=O)2OH、-N(C1-C6Alkyl)2、- C (=O) C1-C6Alkyl or-C (=O) C1-C6Alkoxy；U is C；W is H；R7For H；And R8For H.
In some embodiments, each R1It independently is H, C1-C3Alkyl, C1-C3Alkoxy ,-CN ,-OH, halogen ,- NH2Or-CF3, wherein r is 1,2,3,4 or 5；Each R2And R3It independently is H, C1-C3Alkyl ,-CN ,-OH, halogen ,-N (C1-C3 Alkyl)2、-NH2Or-CF3, wherein n is 1,2,3 or 4；Each R4And R5It independently is H, C1-C3Alkyl ,-CN ,-OH, halogen ,- NH2Or-CF3, wherein n is 1,2,3 or 4；Y is H ,-CN ,-OH, F, Cl or Br；X is O；Z is O；Q is selected from naphthyl and phenyl Aryl；Or selected from following heteroaryl：Benzimidazolyl, benzoxazolyl, imidazole radicals, indazolyl, indolinyl, indoles Base, isoquinolyl, isoxazolyl, oxazolyls, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, Pyrrole radicals, pyrrole radicals, thienyl and triazolyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, wherein t be 0,1,2, 3rd, 4 or 5；Each R6It independently is H, C1-C3Alkyl ,-CN ,-OH, halogen ,-NH2、-CF3、C1-C3Alkoxy ,-N (=O)2、-C (=O) OH ,-O-S (=O)2OH、-N(C1-C3Alkyl)2,-C (=O) C1-C3Alkyl or-C (=O) C1-C3Alkoxy；U is C；W For H；R7For H；And R8For H.
In some embodiments, each R1It independently is H, C1-C3Alkoxy ,-OH, halogen ,-NH2Or-CF3, wherein r For 1,2,3,4 or 5；Each R2And R3It independently is H, C1-C3Alkyl ,-OH ,-N (C1-C3Alkyl)2Or halogen, wherein n are 1,2 Or 3；Each R4And R5It independently is H, C1-C3Alkyl ,-CN or halogen, wherein n are 1,2 or 3；Y is H ,-OH, F, Cl or Br；X For O；Z is O；Q is the aryl selected from naphthyl and phenyl；Or selected from following heteroaryl：Benzimidazolyl, imidazole radicals, indyl, Oxazolyl, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, pyrrole radicals, thienyl And triazolyl；Wherein aryl or heteroaryl are optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；Each R6It independently is H、C1-C3Alkyl, C1-C3Alkoxy ,-OH, halogen ,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、-N (C1-C3Alkyl)2,-C (=O) C1-C3Alkyl or-C (=O) C1-C3Alkoxy；U is C；W is H；R7For H；And R8For H.
In some embodiments, each R1It independently is H, methoxyl group, ethyoxyl, F, Cl, Br ,-NH2Or-CF3, wherein R is 1,2,3,4 or 5；Each R2And R3H, F, Cl or Br independently are, wherein n is 1 or 2；Each R4And R5Independently be H, F, Cl or Br, wherein n are 1 or 2；Y is H；X is O；Z is O；Q is phenyl, pyridazinyl, pyridine radicals, pyrimidine radicals or triazolyl, and its is each Optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；Each R6It independently is H, F, Cl or Br；U is C；W is H；R7For H；And R8For H.
In some embodiments, each R1F, Cl or Br independently are, wherein r is 1,2,3,4 or 5；Each R2And R3Solely It is on the spot H, F, Cl or Br, wherein n is 1；Each R4And R5H, F, Cl or Br independently are, wherein n is 1；Y is H；X is O；Z is O；Q is phenyl, pyridazinyl, pyridine radicals, pyrimidine radicals or triazolyl, and it is each optionally by-(R6)tSubstitution, wherein t be 0,1,2, 3rd, 4 or 5；Each R6It independently is H or F；U is C；W is H；R7For H；And R8For H.
In some embodiments, each R1For F, wherein r is 1,2,3,4 or 5；R2And R3It is that H and n are 1；R4And R5 It is that H and n are 1；Y is H；X is O；Z is O；Q is phenyl, pyridazinyl, pyridine radicals, pyrimidine radicals or triazolyl, and it is each optional Ground quilt-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；Each R6It independently is H or F；U is C；W is H；R7For H；And R8For H。
Covered by Formulas I and include but is not limited to double benzene available for the illustrative example of the compound in method described herein This ketoamine (U C；R is 0；R2And R3It is H；N is 1；R4And R5It is H；P is l；W is H；Y is H；X is O；Z is O；R7For H；Q For phenyl；T is 0；And R8For H), hydroxyl mesocarb (U C；R is 0；R2And R3It is H；N is 1；R4And R5It is H；p For l；W is H；Y is H；X is O；Z is O；R7For H；Q is phenyl；T is l；R6For-the OH in contraposition；And R8For H) or dihydroxy Base mesocarb (U C；R is 0；R2And R3In one be H and R2And R3In another be-OH；N is l；R4And R5It is H；P is l；W is H；Y is H；X is O；Z is O；R7For H；Q is phenyl；T is l；R6For-the OH in contraposition；And R8For H).
In some embodiments, compound or its pharmaceutically acceptable salt are selected from any of following or a variety of (including its any enantiomter)：
In some embodiments, compound or its pharmaceutically acceptable salt are selected from any of following or a variety of (including its any enantiomter)：
In some embodiments, compound is not mesocarb；Hydroxyl mesocarb；This ketone of the double benzene of dihydroxy Amine；N- phenylcarbamoyls -3- (benzyl)-sydnone imines；N- (3', 4'- dichlorophenyl) carbamoyl -3- benzene second Base-sydnone imines；N- (rubigan) carbamoyl -3- phenethyl sydnone imines；N- (m-trifluoromethyl) amino first Acyl group -3- phenethyl sydnone imines；3- (benzyl) sydnones Asia amine-n-phenylcarbamoyl；3- (p- Methyl-benzvl) Sydnone Asia amine-n-phenylcarbamoyl；3- (phenyl propyl) sydnones Asia amine-n-phenylcarbamoyl；3- is (to carboxyl Benzyl) sydnone Asia amine-n-phenylcarbamoyl；3- (p- luorobenzyl -1) sydnone Asia amine-n-phenylcarbamoyl； 3- phenethyl sydnones Asia amine-n-(3'-4'- Dichloro-phenyls) carbamoyl；It is sub- with 3- (p- nitrophenethyl)-sydnone Amine-n-(3', 4'- dinitro-phenyl) carbamoyl；Or its pharmaceutically acceptable salt.
It should be understood that compound as described herein is merely illustrative, and it is not intended to the scope limit of claims Due to only those compounds.
Compound as described herein can be prepared by technique of organic chemistry known to persons of ordinary skill in the art.Example Such as, compound as described herein can be such as such as British Patent No. 1,262,830, U.S. Patent Application Publication No. 2008/0319030 With prepared described in U.S. Patent Application Publication No. 2011/0288137, these patents are incorporated herein by reference in their entirety.
The preparation of compound as described herein can relate to the protection and deprotection of various chemical groups.For protection and remove-insurance The selection of the needs and suitably protecting group of shield can be readily determined by those skilled in the art.Blocking group chemistry is found in Such as T.W, Greene and P.G.M, Wuts, Protective Groups in Organic Synthesis, the 3rd edition, Wiley＆Sons, Inc., New York (1999), the document is incorporated herein by reference in their entirety.Suitable hydroxy-protective group Including but not limited to t-butyldimethylsilyl (TBS), methoxy ether (MOM), THP trtrahydropyranyl ether (THP), uncle Butyl ether, allyl ether, benzylic ether, t-butyldimethylsilyl ether (TBDMS), t-butyldiphenylsilyl ether (TBDPS), acetic acid esters etc..
Compound as described herein also includes the derivative referred to as prodrug, and the derivative can be by modifying as follows It is prepared by the functional group that is present in compound：Which causes trim to be cracked into parent chemical combination with routine operation or in vivo Thing.Prodrug is intended to the carrier for including any covalent bonding, and when applying such prodrug to mammalian subject, the carrier is in body Interior release active parent drug as described herein.The example of prodrug includes compound as described herein, and the compound contains attached One or more molecular moieties of the hydroxyl of the compound, amino, sulfydryl or carboxyl are connected to, and when being applied to patient, Crack in vivo and form free hydroxyl group, amino, sulfydryl or carboxyl respectively.The example of prodrug includes but is not limited to as described hereinization Acetic ester derivative, carbamate derivatives and the benzoate derivatives of alcohol functional group and amine functional group in compound.Prodrug Prepare and use is in T.Higuchi et al., " Pro-drugs as Novel Delivery Systems, " A.C.S.Symposium Series volume 14 and Bioreversible Carriers in Drug Design, Edward B.Roche are edited, American Pharmaceutical Association and Pergamon Press, There is discussion in 1987, this two documents are incorporated herein by reference in their entirety.
The disclosure also provides the composition for including one or more compound of formula I.In some embodiments, said composition It is the pharmaceutical composition for including pharmaceutically acceptable carrier.
In some embodiments, what said composition can include therapeutically effective amount is optionally in the described herein of purified form Compound (optionally as described herein to exceed a kind of compound) and proper amount of pharmaceutically acceptable carrier.
Carrier includes diluent, adjuvant, excipient or the other mediums applied together with compound as described herein.This Class pharmaceutical carrier can be liquid, Ru Shui and oil, include oil, animal, plant or synthesis source those, such as peanut oil, big Soya-bean oil, mineral oil, sesame oil etc..Pharmaceutical carrier can be salt solution, Arabic gum, gelatin, gelatinized corn starch, talcum, keratin, colloidal state Silica, urea etc..In addition, auxiliary agent, stabilizer, thickening agent, lubricant and colouring agent can be used.When being applied to patient, Compound and pharmaceutically acceptable carrier as described herein are suitably to be sterile.When compound administered intraveniously, water It is suitable carrier.Saline solution and aqueous dextrose and glycerite can also be used as being used in particular for Injectable solution Liquid-carrier.Suitable pharmaceutical carrier also includes excipient, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, face Powder, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, skimmed milk power, glycerine, propylene, glycerine, water, Ethanol etc..If desired, this composition also contains a small amount of wetting agent or emulsifying agent or pH buffer.
This composition can be in the form of the following：Solution, supensoid agent, emulsion, tablet, pill, piller, capsule, the glue containing liquid Capsule, powder, sustained release preparation, suppository, emulsion, aerosol, spray, supensoid agent or any other form being adapted in use to.One In individual embodiment, pharmaceutically acceptable carrier is capsule (see, for example, U.S. Patent number 5,698,155).Suitable drug carries Other examples of body are described in Remington ' s Pharmaceutical Sciences, A.R.Gennaro (editor) Mack In Publishing Co..
In some embodiments, compound as described herein is formulated as being suitable into human vein according to conventional program The pharmaceutical composition of administration.The compound as described herein for being commonly used for intravenously applying is in the water-based buffer solution of sterile isotonic Solution.When necessary, composition can also include solubilizer.Composition for intravenously applying is numb optionally comprising part Liquor-saturated dose of such as lidocaine (lidocaine) is to mitigate the pain of injection site.Generally, the composition with unit dosage forms by individually or Supply is mixed, for example, as dry in ampoule or anther sac (sachette) of the gas-tight container as indicated activating agent quantity Dry freeze-dried powder or without the form of aqueous concentrate.When compound as described herein will be applied by being transfused, it can for example be equipped with nothing The water of bacterium pharmaceutical grade or the infusion bottle of salt solution are distributed.When compound as described herein is applied by injecting, it is possible to provide injection With sterilized water or the ampoule of salt solution so that the composition can be mixed before administration.
Composition as described herein can also be prepared for orally administering.For oral delivery composition can be in for example with Lower form：Tablet, lozenge, water-based or Oil suspensions, granule, powder, emulsion, capsule, syrup or elixir.Orally administer Composition can contain one or more optional reagents, for example, sweetener, such as fructose, aspartame (aspartame) or saccharin； Flavor enhancement, such as peppermint, wintergreen or cherry；Colouring agent；And preservative, to provide pharmaceutically tasty preparation.In addition, it is in piece to work as When agent or pill, composition can be coated to postpone disintegration and absorption in the gastrointestinal tract, thus carried within the extension period For continuous action.The selective permeable membrane for surrounding osmotically active driving compound is also suitable for as described hereinization orally administered Compound.In platform behind these, the fluid of the environment from capsule surroundings is sucked by driving compound, the driving compound It is swelled and reagent or reagent composition is displaced through hole.These delivery platforms can provide the delivering feature of substantially zero level, this It is opposite with the sharp peaks characteristic (spiked profile) of immediate release formulation.Time delay material, such as glycerol monostearate also can be used Ester or tristerin.Orally administered composition may include standard vector, as mannitol, lactose, starch, magnesium stearate, saccharin sodium, Cellulose, magnesium carbonate etc..Examples of such carriers is suitably pharmaceutical grade.
The amount of the effective compound as described herein in terms of particular condition or symptom disclosed herein is treated will be taken Certainly in illness or the property of symptom, and can be determined by standard clinical techniques.In addition, external or in vivoassay is optionally It is used to help differentiate optimal dosage range.The exact dose being ready to use in composition will also depend on route of administration and disease Or the seriousness of illness, and should be determined according to the situation of the judgement of practitioners and every patient.However, for oral The Suitable dosage ranges of administration are typically the compound as described herein per about 0.001 milligram to 200 milligrams of kg body weight.One In a little embodiments, oral dose be 0.01 milligram to 70 milligrams of every kg body weight or per 0.1 milligram of kg body weight to 50 millis Gram or per 0.5 milligram to 20 milligrams of kg body weight or per 1 milligram to 10 milligrams of kg body weight.In some embodiments, mouth It is the compound as described herein per 5 milligrams of kg body weight to take dosage.Dosage amount as described herein refers to the total amount applied；That is, If exceeding a kind of compound using as described herein, dosage corresponds to the total amount for the compound as described herein applied.Mouthful Active component of the oral compositions containing 10 weight % to 95 weight %.
It is every 0.01 milligram to 100 milligrams of kg body weight, every thousand for intravenous (i.v.) Suitable dosage ranges applied Gram 0.1 milligram to 35 milligrams of body weight and per 1 milligram to 10 milligrams of kg body weight.Suitable dosage ranges for intranasal administration are usual It is about 0.01pg/kg body weight to 1mg/kg body weight.Suppository usually contains this paper institutes of every 0.01 milligram to 50 milligrams of kg body weight The compound stated and comprising the active component in the range of 0.5 weight % to 10 weight %.For intracutaneous, intramuscular, intraperitoneal, Subcutaneously, Epidural cavity, sublingual, big intracerebral, intravaginal, applied dermally or by sucking the recommended dose applied in every kg body weight In the range of 0.001 milligram to 200 milligrams.Compound as described herein is used for the suitable dose of local application at 0.001 milligram To in the range of 1 milligram, this depends on the region that the compound is administered.Can be from from external or animal model test system Dose-effect curve extrapolation effective dose.Such animal model and system are known in the art.
The disclosure additionally provides drug packages or kit, and it includes and is filled with one or more compounds as described herein One or more containers.Such container is optionally with notice, manufacture, use of the notice in supervision medicine or biological product Or form as defined in the government organs of sale, and the notice reflects the mechanism and manufacture, use or sale is criticized for people's administration It is accurate.In some embodiments, kit exceedes a kind of compound equipped with as described herein.In some embodiments, reagent Any of box is equipped with compound as described herein and another therapeutic agent, as those described herein.
Compound as described herein can determine desired treatment or prevention activity in vitro and in vivo in people using preceding.Example Such as, external test can be used for determining whether apply specific compound as described herein or the combination of compound as described herein is suitable to Treat dyskinesia.Animal model system also can be used to confirm that compound as described herein is effective and safe.
Other methods will be known to those skilled in the art and in the scope of the present disclosure.
In some embodiments, compound as described herein can be (that is, one or more with least one other therapeutic agent Other therapeutic agents) use and/or prepare in combination treatment.Compound and additional therapeutic agent superposability as described herein or Synergistically work.In some embodiments, the administration of composition and another therapeutic agent comprising compound as described herein It is administered simultaneously, another therapeutic agent can be the part with compound identical composition as described herein or different components. In another embodiment, the composition comprising compound as described herein is applied before or after another therapeutic agent is applied. In some embodiments, combination treatment is related in composition of the administration comprising compound described herein and comprising another therapeutic agent Composition between alternately, for example, with by relevant with certain drug toxicity minimum.Every kind of medicine or therapeutic agent are applied It can be such as 1 month, 3 months, 6 months or 1 year with the duration.In certain embodiments, when combination as described herein When another therapeutic agent of thing and the adverse side effect including potentially generation including but not limited to toxicity is administered simultaneously, therapeutic agent can Advantageously applied with being brought down below the dosage for the threshold value for triggering adverse side effect.
In some embodiments, additional therapeutic agent is：1) anti-Parkinson agent；2) it is used for the medicament for treating dyskinesia； And/or 3) induce the medicament of other types of dyskinesia.One or more in these medicaments can be with chemical combination as described herein Thing combines in identical composition, preparation or formulation, or is combined into mammal single administration (such as being administered simultaneously).This A little medicaments can have indicated that for the amount of mammal or to be used less than the dosage of acceptable dosage.
In some embodiments, anti-Parkinson agent is：1) it is used for the medicament that dopamine substitutes, including but not limited to L- is more Bar and L-3,4 dihydroxyphenylalanine/carbidopa (carbidopa)2) dopamine uptake retarding agent, do not reach including but not limited to Non- Buddhist nun (modafinil)Benzimidazole thiophanate phenyl cyclohexyl piperidine (benocyclidine) and amfonelic acid (amfonelic acid)；3) dopamine agonist, including but not limited to apomorphine (apomorphine) (Apokyn, Ixense, Spontane and Uprima), bromocriptine (bromocriptine) (Parlodel and Cycloset), Cabergoline (cabergoline) (Dostinex and Cahaser), lisuride (lisuride) (Dopergin, Proclacam and Revanil), pergolide (pergolide) (Permax), Ropinirole (ropinirole) (Requip, Ropark and Adartrel), Pramipexole (pramipexole) (Mirapex, Mirapexin and Sifrol) and INN (rotigotine)(Neupro)；4) anticholinergic, including but not limited to benzhexol (trihyexyphenidyl) (Artane, Apo-Trihex, Parkin and Pacitane) and benzatropine (benzatropine) (Cogentin)；5)MAO Inhibitor, including but not limited to selegiline (selegiline) (Anipryl, L-depreny], Eldepryl, Emsam and ) and ginkgo Zelapar；With 6) COMT inhibitor, including but not limited to Tolcapone (tolcapone) (Tasmar) and Entacapone (entacapone)(Comtan)。
In some embodiments, the medicament for treating dyskinesia is：1) glutamate receptor antagonists, including but not It is limited to amantadine (Symmetrel), dextrorphan, dextrorphan fragrant (dextromorphan), MK-801 (Dizocilpines ) and Co-101,244/PD-174,494 (Dizocilpine)；2) ampa receptor, including but not limited to retigabine (retigabine) (Trobalt, Potiga), Flupirtine (flupirtine) (Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo and Metanor), Topiramate (topirimate) (Topamax), GYK-47,261 and IEM- 1460；3) mGluR5, including but not limited to MRZ-8676, AFQ056 (Mavogiurant), ADX-48,621,2- methyl -6- (phenylene-ethynylene) pyridine (MPEP) and 3- ((2- methyl -4- thiazolyls) acetenyl) pyridine (MTEP)；4) glutamate discharges Inhibitor, including but not limited to Riluzole (riluzole)With Naftazone (naftazone)；5) opium sample thing Matter, including but not limited to U50-488, morphine (Avinza, Kadian, Oramorph, Roxanol and Kapanol), pethidineWith methadone (methadone) (Symoron, Dolophine, Amidone, Methadose, Physeptone、Heptadon)；6) serotonergic agent, including but not limited to buspirone (Buspar), Clozapine (clozapine) (Clozaril), Quetiapine (quetiapine) (Seroquel, Xeroquel and Ketipinor), MDMA (3,4- methylenedioxy-N- meths) (Ecstasy), piperazine Ma Selin (pimavenserin), ritanserin (ritanserin), Citalopram (citalopram) (Celexa, Cipramil) and Prozac (fluoxetine) (Prozac、Sarafem、Fontex)；7) GABA compounds, including but not limited to diazepam (diazepam) (Diastat, ) and zolpidem (zolpidem) (Ambien, Ambien CR, Intermezzo, Stilnox and Sublinox) Valium；8) gland Glycoside compound, including but not limited to istradefylline (istradefylline) and Rui Denante (preladenant)；9) hemp Element, including but not limited to Rimonabant (rimonabant) (Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, Rimoslim, Zimulti and Riomont) and nabilone (nabilone) (Cesamet)；10) on kidney Parathyrine energy agent, including but not limited to idazoxan (Idazoxan), yogimbine (Yohimbine) (Yocon), rauwolscine (Rauwolscine) (different yogimbine, corynanthidine and mesoyohimbine (corynanthidine)), Fei Pamei azoles (Fipamezole) and Propranolol (propanolol) (Inderal, Inderal LA, Avlocardyl, Deralin, Dociton、Inderalici、InnoPran XL、Sumial、Anaprilinum、Bedranol SR)；11) histamine, including but It is not limited to famotidine (famotidine) (Pepcid), Yi Mei general (immepip) and Yi Mei are replaced special (Imetit)；12) courage Alkali energy agent, including but not limited to nicotine, Rivastigmine (rivastigmine) (Exelon) and donepezil (donepezil) (Aricept)；With 13) another medicament, including but not limited to TAM (tamoxifen) (Nolvadex, Istubal, Valodex), silaenafil (sildenafil) (Viagra) and Uk-343,664.
In some embodiments, the medicament for inducing other types of dyskinesia is major tranquilizer, including but unlimited In chlorpromazine (Thorazine, Largactil, Megaphen), Metoclopramide (metoclopramide) (Reglan), different Promazine (Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan and Sominex), Olanzapine (olanzapine) (Zyprexa), Risperidone (risperidone) (Risperdal), Clozapine (Clozaril), Aripiprazole (aripiprazole) (Abilify, Aripiprex)。
In some embodiments, additional agent is not Anti-epileptics.Anti-epileptics is selected from carbamazepine (carbamazepine), Lamotrigine (lamotrigine), phenobarbital (phenobarbital), phenytoinum naticum (phenyloin), Topiramate, valproate and Zonisamide (zonisamide).In some embodiments, anticonvulsant or Anti-epileptics be selected from carbamazepine, Gabapentin (gabapentin), Lamotrigine, Levetiracetam (levetiracetam), Oxcarbazepine (oxcarbazepine), phenytoinum naticum, Pregabalin (pregabalin), rufinamide (rufinamide), the third penta Hydrochlorate and Topiramate.In some embodiments, anticonvulsant or Anti-epileptics are selected from Gabapentin, Lamotrigine, Zuo Yila Western smooth, Pregabalin, rufinamide, valproate and Topiramate.The example of anticonvulsant or Anti-epileptics includes but is not limited to The following medicament non-exclusively described by binding mode or chemical classes：A) AMPA antagonists, as AMP-397, E-2007, NS-1209, talampanel (talampanel), pyrrole Lun Panai (perampanel) etc.；B) Benzodiazepine (benzodiazepine), diazepam, Lorazepam (lorazepam), Clonazepam (clonazepam), Clobazam (clobazam), chlorine Zhuo hydrochlorate (clorazepate), midazolam (midazolam), Nimetazepam (nimetazepam), nitre Dissolve (nitrazepam), Temazepam (temasepam) etc. in west；C) barbiturate, such as phenobarbital, amytal (amobarbital), mebaral, Primidone (primidone), barbexaclone sodium (barbexaclone sodium), Metharbital (metharbital), amobarbital (pentobarbital) etc.；D) valproate (including derivative of fatty acid), Such as valproic acid, valproate semisodium, valpromide, double valproates (divalproex), Valnoctamide (valnoctamide)； E) GABA related agents, such as Gabapentin (2- [l- (amino methyl) cyclohexyl] acetic acid), Pregabalin ((S) -3- (amino first Base) -5- methyl is sour), sabril etc.；F) AED, such as Losigamone (losigamone), retigabine, rufinamide (1- [(2,6- difluorophenyls) methyl-l] triazole -4- formamides), SPD-421 (DP-VPA), T-2000, XP-13512 etc.；G) imido Base stilbene (iminostilbene), such as carbamazepine, O'Casey equality；H) hydantoins, as dilantin sodium, phenytoinum naticum, U.S. sweet smell are appropriate English (mephenytoin), fosphenytoin sodium (fosphenyloin sodium), Ethotoin (ethotoin) etc.；H) NMDA is short of money Anti-agent, such as SPM937 (harkoseride)；I) sodium channel inhibitor, such as BIA-2093, C0-102862, Lamotrigine； J) succinimide, such as mesuximide (methsuximide), ethymal, phensuximide, mesuximide (mesuximide)；K) carboxylic Acid, such as Tiagabine (tiagabine)；L) AEDS, such as acetazolamide, clormethiazole (clomthiazole), ethanedisulphonate (edisilate), Zonisamide, Felbamate (felbamate), such as Topiramate, Tiagabine, Levetiracetam, Bu Waxitan (briveracetam), GSK-362115, GSK-406725, ICA-69673, CBD hemp derivative, isovaleramide (NFS- 1776), RWJ-333369 (carisbamate (carisbamate)), FCE-26743A (safinamide), plug Qu Xitan (seletracetam), soretolide (soretolide), Stiripentol (stiripentol), valrocemide (valrocemide) etc.；M) oxazolidinedione, such as trimethadione (trimethadione), paramethadione (paramethadione), ethadione (ethadione) etc.；N) pyrrolidines, such as Levetiracetam；O) sulfonamide, such as second Acyl azoles amine, methazolamide, Zonisamide, easypro thiazine (sultiame) etc.；P) aminobutyric acid etc.；Q) list of sulfamate substitution Sugar, such as Topiramate (2,3:Double -0- (l- methyl the ethylidene)-Beta-D-Fructopyranose sulfamates of 4,5-)) etc.；R) formamide, Such as carbamazepine, Oxcarbazepine, rufinamide；S) aromatics allyl alcohol, such as Stiripentol；T) urea, such as phenacemide, benzene fourth Uride etc.；U) phenyl triazine, such as Lamotrigine；V) carbamate, as Emylcamate (emylcamate), Felbamate, Meprobamate etc.；W) pyrrolidines, such as Bu Waxitan, Levetiracetam, Nefiracetam (nefiracetam), plug Qu Xitan；With X) eugenol, such as (Coryophyllic acid), phenyl eugenol, benzyl eugenol and phenethyl eugenol.
The method that the disclosure also provides the dyskinesia or another illness for the treatment of mammal, it is included to there is this needs Mammal applies Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or the Formulas I d-2 of effective dose Compound：
Or its pharmaceutically acceptable salt, wherein：U is C or N；Each R1It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (= O)OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulphur Acyl group, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl or Dialkyl amido Sulfinylalkyl, wherein r are 0,1,2,3,4 or 5；Each R2And R3It independently is H, C1-C6Alkyl, C2-C6 Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-C (=O) OH、-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl sulfonyl Base, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, aminosulfonyl Base, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl oxygen Base, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, monoalkyl Amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl, Dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein n are 0,1,2,3 or 4；Each R4And R5Independently For H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, halo Alkyl ,-NO2,-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, first Amide groups, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino Asia sulphur Acyl group, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide oxygen Base, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino sulphur Acyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, monoalkyl ammonia Base Sulfinylalkyl, dialkyl amido Sulfinylalkyl, aryl or aryl C1-C6Alkyl, wherein p are 0,1,2,3 or 4；W For H or C1-C6Alkyl；Y is H, C1-C6Alkoxy, C1-C6Alkylthio group ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2、-C (=O) OH ,-NH2、-CF3、-NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H, alkoxy carbonyl group, formamido, alkyl Sulfonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, alkyl monosubstituted amino sulfinyl, amino sulphur Acyl group, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxysulfonamide epoxide, alkoxy sulphonyl Epoxide, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, amino-sulfonyl alkyl, single alkane Base amino-sulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, alkyl monosubstituted amino Sulfinylalkyl Or dialkyl amido Sulfinylalkyl；X is O or S；Z is O or S；R7For H or halogen；Q is H, C1-C6Alkyl, aryl, C1-C6 Alkylaryl, C3-C6Cycloalkyl or heteroaryl, it is each optionally by-(R6)tSubstitution, wherein t are 0,1,2,3,4 or 5；R8For H Or C1-C6Alkyl；And each R6It independently is H, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C1-C6Alkane Sulfenyl ,-CN ,-OH ,-SH, halogen, haloalkyl ,-NO2,-N (=O)2,-C (=O) OH ,-NH2、-CF3,-O-S (=O)2OH、- NH(C1-C6Alkyl) ,-N (C1-C6Alkyl)2,-C (=O) H ,-C (=O) C1-C6Alkyl ,-C (=O) C1-C6Alkoxy, alcoxyl carbonyl Base, formamido, alkyl sulphonyl, alkylsulfonyloxy, amino sulfinyl, dialkyl amido sulfinyl, monoalkyl ammonia Base sulfinyl, amino-sulfonyl, monoalkylaminosulfonyl, dialkyl amino sulfonyl, alkyl sulfonyl-amino, hydroxyl sulphur Acyloxy, alkoxy sulfonyloxy, alkylsulfonyloxy, hydroxysufonyl, alkyloxysulfonyl, Alkylsulfonylalkyl, ammonia Base Sulfonylalkyl, monoalkylaminosulfonyl alkyl, dialkyl amino sulfonyl alkyl, amino Sulfinylalkyl, single alkane Base amino Sulfinylalkyl or dialkyl amido Sulfinylalkyl；Or its pharmaceutically acceptable salt, wherein another illness Be restless leg syndrome (such as drug-induced property or idiopathic), drug-induced property dystonia, chorea (such as Huntington's disease, Toxin induce property chorea, Sydenham's chorea, chorea gravidarum, Wilson's disease, drug-induced property chorea and Metabolic and endocrine correlation chorea), twitch (such as the twitch of motor tic, voice, simple tics, complexity are taken out Jerk and gilles de la Tourette's syndrome), dystonia (such as acute dystonic, generalized dystonia, Focal dystonias, section Property dystonia, property dystonia, osculant dystonia, psychogenic dystonia and acute dystonic reaction), Sodemytopic Parkinson's diseases, stereotyped movement disorder (such as related to autism dyskinesia, hereditary motor obstacle With childhood dyskinesia), compulsive disorder, narcolepsy (such as dampinging off), propagated spongiform encephalopathy (such as Ke-refined Er Shi Disease and kuru), Neuroacanthocytosis, epileptic attack and convulsions, athetosis (such as with Huntington's disease, asphyxia, The icterus neonatorum athetosis related to apoplexy) or cerebral paralysis.
The method that the disclosure also provides treatment and/or prevention dyskinesia.
In some embodiments, to the mammal with dyskinesia and/or the illness relevant with dyskinesia (such as People) apply the composition as described herein comprising compound as described herein and pharmaceutically acceptable carrier.
The disclosure is provided by being carried out to the composition comprising compound as described herein of patient therapeuticallv's effective dose The method for the treatment of and prevention.Patient is mammal, including but not limited to ox, horse, sheep, pig, chicken, turkey, quail, cat, dog, Mouse, rat, rabbit, cavy etc., and be more suitably people.
This composition palatable clothes comprising one or more compounds as described herein are applied.Compound as described herein is also By any other approach can be facilitated to apply, for example, by infusion or bolus infusion, by via epithelium or mucocutaneous Lining (for example, oral mucosa, mucous membrane of rectum and intestinal mucosa etc.) is absorbed to apply, and can be applied together with another bioactivator With.Using can be systemic or local.Various delivery systems are known, for example, being encapsulated in liposome, particulate, micro- In capsule, capsule etc., and available for using compound as described herein.In some embodiments, applied herein to patient Described exceedes a kind of compound.Application process is including but not limited to intracutaneous, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, hard Film is outer, oral cavity, sublingual, intranasal, big intracerebral, intravaginal, percutaneous, per rectum, by suction or local, particularly to ear, nose, eye Or topical application.Mode of administration is judged by practitioners, and will depend partially on the position of Medical Condition.In majority In the case of, administration will cause compound as described herein to discharge into blood flow.In some embodiments, administration frequency is daily Once (qd).
In some embodiments, it may be desirable to control one or more compound local applications as described herein to needs The region for the treatment of.This can be realized for example, by (and not in a manner of limiting) in the following manner：By perioperative local infusion, Such as the local application that Post operation is combined with wound dressing, by injection, by means of conduit, by means of suppository or by means of implantation Thing, the implant are porous, non-porous or gel-like material, including film, such as silicon rubber (sialastic) film, or fiber.
It can also use pulmonary administration, such as the preparation by using inhalator or sprayer and containing Alevaire, or via It is irrigated in fluorocarbon or the Curosurf of synthesis.In certain embodiments, compound as described herein Suppository can be deployed into traditional adhesive and medium such as triglycerides.
In another embodiment, compound as described herein can in vesica, particularly in liposome delivering (referring to Langer,Science,1990,249,1527-1533；Treat et al., in Liposomes in the Therapy of In Infectious Disease and Cancer, Lopez-Berestein and Fidler (editor), Liss, New York, The 353-365 pages (1989)；Lopez-Berestein, is shown in ibid, the 317-327 pages, generally sees ibid).
In some embodiments, compound as described herein can deliver in controlled release system.In some embodiments, Pump can be used (referring to Langer, to see above；Sefton,1987,CRC Crit.Ref Biomed.Eng.14:201； Buchwald et al., 1980, Surgery88:507Saudek et al., 1989, N Engl.J.Med.321:574).In some realities Apply in scheme, polymeric material can be used (referring to Medical Applications of Controlled Release, Langer With Wise (editor), CRC Pres., Boca Raton, Fla. (1974)；Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (editor), Wiley, New York (1984)； Ranger and Peppas, 1983, J.Macromol.Sci.Rev.Macromol.Chem.23:61；Referring further to Levy et al., 1985,Science 228:190；During et al., 1989, Ann.Neurol.25:351；Howard et al., 1989, J.Neurosurg.71:105).In some embodiments, controlled release system can be placed in compound as described herein target it is attached Closely, a part of systemic doses therefore are only needed (see, for example, Goodson, in Medical Applications of In Controlled Release, see above, volume 2, the 115-138 pages (1984)).It can be used and be discussed in Langer, 1990, Science249:Other controlled release systems in summary 1527-1533).
In some embodiments, compound, composition, preparation and/or formulation can be used for treatment and/or prevention motion barrier Hinder.In some embodiments, dyskinesia is levodopa dyskinesia (LID).LID, which may be present in, have been taken In the patient with Parkinson's disease of levodopa longer period of time.Three kinds of forms of dyskinesia are based on it in oral dose L-3,4 dihydroxyphenylalanine after process and performance be classified：I) aperiodicity (off-period) dystonia is (when the blood plasma water of L-3,4 dihydroxyphenylalanine When flat relatively low, the motion of generation can not be related before starting to the complete effect of L-3,4 dihydroxyphenylalanine)；Ii) Bipolar dyskinesia (betides When plasma levels of levodopa rises or falls；The form be usually dystonia or ballism；L-3,4 dihydroxyphenylalanine is reduced without sound Should)；And iii) peak dose dyskinesias (LID most common form；It is related to stable L-3,4 dihydroxyphenylalanine blood plasma level).One In a little embodiments, dyskinesia is chronic motor disorder or tardive dyskinesia.Tardive dyskinesia occurs with anti- After mental disease agent medicine such as haloperidol or amoxapine (amoxapine) treatment.Tardive dyskinesia frequently involve not with Meaning sip lip, repetitious lip and the tongue of sticking up stretches out.In some embodiments, dyskinesia be possible be with herpes simplex virus The related orofacial dyskinesia (for example, rabbit syndrome) of the lasting duplication of 1 type.
In some embodiments, compound, composition, preparation and/or formulation can be used for treating and/or preventing other diseases Disease.In some embodiments, illness is restless leg syndrome (for example, drug-induced property or idiopathic).In some embodiment party In case, illness is drug-induced property dystonia.In some embodiments, illness is chorea (for example, Huntington's disease； Toxin induction property chorea；Sydenham's chorea；Chorea gravidarum；Wilson's disease；Drug-induced property chorea；And Metabolic and endocrine correlation chorea).In some embodiments, illness is twitch (for example, motor tic, voice Property twitch, simple tics, complexity twitch and gilles de la Tourette's syndrome).In some embodiments, illness is dystonia (for example, acute dystonic；Generalized dystonia；Focal dystonias；Segmental dystonias；Property dystonia；In Between type dystonia；Psychogenic dystonia and acute dystonic reaction).In some embodiments, illness is Sodemytopic Parkinson's diseases.In some embodiments, illness is stereotyped movement disorder (for example, related to autism Dyskinesia；Hereditary motor obstacle and childhood dyskinesia).In some embodiments, illness is compulsive disorder. In some embodiments, illness is narcolepsy (for example, dampinging off).In some embodiments, illness is propagated sea Continuous shape encephalopathic (for example, Creutzfeldt-Jakob disease and kuru).In some embodiments, illness is Neuroacanthocytosis. In some embodiments, illness is epileptic attack and convulsions.In some embodiments, illness be athetosis (for example, The athetosis related to Huntington's disease, asphyxia, icterus neonatorum and apoplexy).In some embodiments, illness is big Cerebral paralysis.
In some embodiments, compound as described herein and/or composition are not used in treatment：Epilepsy；Op parkinson's Disease；Lung pathology, such as pulmonary edema；Ischemia-reperfusion injury；Heart conditions, such as acute decompensation DHF and Cardiorenal syndrome；Hyperprolactinemia (BrE), hyperprolactinemia (ArnE) and microprolactinoma；Pain, including chronic pain Pain or neuropathic pain；Tonicity psychosis, dyskinesia, restless leg syndrome and associated dyskinesias；Stress, chronic trauma Stress disorders, anxiety disorder, compulsive disorder, post-natal depression afterwards；Schizophrenia, manic disorder, bipolar disorder and The disturbance of emotion；Perform function obstacle, such as ADHD, gilles de la Tourette's syndrome and autism；Cocaine, amphetamine (amphetamine), alcohol dependence and Addictive Behaviors, such as pathological gambling；Neuroendocrine regulation obstacle；Inflammatory condition, Autoimmune disease and rheumatism；Neoplastic condition, such as pituitary carcinoma, macroprolactinoma；Visual sense feeling illness, colour vision lack Fall into；And ejaculatory dysfunction and related sexual dysfunction.
In some embodiments, compounds as disclosed herein is not combined with L-3,4 dihydroxyphenylalanine for treating Parkinson's disease； Or do not combined with selective serotonin reuptake inhibitor (SSRI) for treating depression and/or cocaine abuse and habituation； Or not with dopamine D 2 antagonist-combination for treating schizophrenia；Or do not combined with cholinergic conditioning agent for treating A Er Thatch sea Mo's disease or wherein patient suffer from the Other diseases or symptom of cognitive defect；Or do not combined with Anti-epileptics for treating late The dyskinesia of hair property.
The notable side effect treated in the presence of L-3,4 dihydroxyphenylalanine not relevant with dyskinesia, including but not limited to low blood pressure；Heart rate It is not normal；Nausea；Gastrointestinal bleeding；Disturbed breathing；Trichomadesis；Disorientation and/or amentia；Extreme emotion state, especially It is anxiety disorder, but also has sexual hyperesthesia；Lively dreamland (vivid dream) and/or insomnia；Acousma and/or visual hallucination； Influence to study；Hypnosia and narcolepsy；With excitant mental disease.In some embodiments, use is as described herein Compound or composition treatment reduce or eliminated the one or more in these side effects.
In addition, the serious side effects in the treatment of Parkinson's disease are the influences that chronic levodopa is applied, including but not It is limited to：Last function deteriorates dosage eventually；Fluctuation with/without；It is stiff during motion；Dosage fails (resistance to the action of a drug)；Peak dose moves Obstacle (levodopa dyskinesia)；Possible thrombocytin loss；Lacked of proper care with possible dopamine.In some embodiment party In case, the one or more in these side effects are reduced or eliminated with compound as described herein or composition treatment.
The disclosure provides the method for treating Parkinson's disease, it include to the people for having this needs apply effective dose as Formulas I a-1 as described herein, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 compound. In some embodiments, Formulas I a-1, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, Formulas I c-2, Formulas I d-1 or the formula applied Id-2 compound is present in any combinations thing disclosed herein.In some embodiments, application of it is any or The people of a variety of compound of formula I also application of L-3,4 dihydroxyphenylalanine.In some embodiments, L-3,4 dihydroxyphenylalanine and compound of formula I are present in same In composition or formulation.
The disclosure provides the method for treating the sleep-disorder of length of one's sleep table for being characterised by being interrupted, it include to The people that having this needs applies Formulas I a-1 as described herein, Formulas I a-2, Formulas I b-1, Formulas I b-2, Formulas I c-1, the Formulas I c- of effective dose 2nd, Formulas I d-1 or Formulas I d-2 compound.In some embodiments, Formulas I a-1, Formulas I a-2, Formulas I b-1, the Formulas I b- applied 2nd, Formulas I c-1, Formulas I c-2, Formulas I d-1 or Formulas I d-2 compound are present in any combinations thing disclosed herein.It is undesirable by It is limited to any particular theory, compound of formula I can work by recovering ortho structure and/or normal circadian rhythm.With changing The example of the relevant sleep-disorder of the sleep rhythm and/or structure of change includes but is not limited to insomnia, restless leg syndrome, breaking-out Property sleeps disease and REM sleep behavior disorder；The illness relevant with neurodegenerative disease, such as Alzheimer's, Parkinson's disease And multiple sclerosis；Relevant destroyed REM sleep obstacle is given up with drug withdrawal, especially alcohol or sedative hypnotics； And the destroyed circadian rhythm relevant with sleep apnea, work in shifts and the time difference.
In order to more effectively understand presently disclosed subject matter, embodiment is provided below.It should be appreciated that these embodiments Purpose is merely to illustrate that, without that should be construed as limiting theme claimed.In these embodiments In, unless otherwise stated, according to Maniatis et al., Molecular Cloning-A Laboratory Manual, the 2 editions, the method described in Cold Spring Harbor Press (1989), implement molecular cloning reaction using commercial reagent With other standard recombinant dna technologies.
The U.S.Provisional serial number 61/786,714 that on March 15th, 2013 submits is incorporated herein by reference in their entirety.
Embodiment
Embodiment 1：The rat model of Parkinson's disease
Neurotoxin 6- hydroxyl dopamines (6-OHDA), which are widely used in Parkinson's disease (PD) animal model, to lure Send out dopaminergic neuron consume.Into medial forebrain bundle, the unilateral 6-OHDA that applies can produce in being injected in animal for 80-90% Raw 90-95% homonymy dopamine neuron consume, causes PD- sample motility dysfunctions.Can with L-3,4 dihydroxyphenylalanine processing compromised animals There is not same-action to the exercise performance in the model.P of Rats D model of the current research in the 6-OHDA L-3,4 dihydroxyphenylalanine processing damaged In have evaluated mesocarb.
Use the Sprague-Dawley female rats (Charles River Laboratories) of 7 to 8 week old.Will be dynamic Thing is randomly assigned to treatment group.Diet is made up of the standard rodent chow and water that can arbitrarily obtain.
5mg/ml solution will be configured in 0.03% ascorbic acid of the 6-OHDA in sterile 0.9%NaCl.By 3 μ L 6- OHDA is injected in medial forebrain bundle from bregma at following stereotactic coordinates：Anteroposterior position (A/P) -4.0mm；Middle side (M/L)- 1.3mm；Abdomen dorsal part (V/D) -8.0mm, relative at the top of skull.
After infringement, rat is recovered two weeks, then test its amphetamine induction property rotary moveable.With 25mg/kg in Amphetamine in salt solution handles animal and recorded 90 minutes in spacious field room.Rat of the rotation more than 4 times only per minute is used In efficacy study.After extra one week, handle rat in different time L-3,4 dihydroxyphenylalanine (Isotec IY0630) and measure exception The appearance of involuntary movement (AIM).
AIM test implementations are as follows：1) weigh rat and injected with L-3,4 dihydroxyphenylalanine/benserazide (10ml/kg, ip)；Can be Through the daily single injection of more days；The administration of test compound or reference compound can also be included；2) rat is placed in sky cage In, start to record a video；3) AIM is evaluated in 4 regions：A) paresthesia epilepsy-incubation period (second) to first time as defined below Visual AIM；B) AIM scorings in 30 minutes；C) AIM scorings in 60 minutes；And d) the anticlockwise number of 30-60 minutes；4) by 0 to 4 Scale is scored and recorded to AIM：I) it is not present；Ii) there is the slight left fore dystonia of grooming；Iii) reasonable hair The excessive left fore dystonia of behavior；Iv) there is the left fore dystonia turned left and enclosed；And v) with or without the continuous of grooming Turn left circle；5) any abnormal clinical sign is recorded；With 6) after 60 minutes, stop recording, rat is returned in foster cage.
As shown in Figure 1A, to previously unilateral based on the 6-OHDA for being subject to selection to the revolving reaction that amphetamine is handled The Sprague-Dawley rats (N=10-11/group) of infringement apply L-3,4 dihydroxyphenylalanine (6mg/kg) once a day, continue 5.Note 60 minutes after penetrating, abnormal involuntary movement (AIM) is scored.Compared to the rat of medium processing, handled with L-3,4 dihydroxyphenylalanine Produce significantly higher AIM scorings.As shown in fig. 1b, compared to the rat of medium processing, once a day mesocarb The processing of (10mg/kg and 30mg/kg) does not cause significant AIM.As shown in Figure 1A and 1B, it is more compared to medium group, L- The significant AIM of Ba Yinqi, and individually mesocarb does not cause significant AIM.These data confirm that empirical tests it is preclinical The foundation of PD models.
Embodiment 2：The reduction of L-3,4 dihydroxyphenylalanine induction property dyskinesia
Receive the rat of unilateral 6-OHDA infringements, Ran Houyong as described above with L-3,4 dihydroxyphenylalanine processing in (the 1st day, 50mg/kg) L-3,4 dihydroxyphenylalanine and testing drug are handled for (the 2nd day, mesocarb or Te Suofenxin).Handled with L-3,4 dihydroxyphenylalanine cause within 2nd it is abnormal not with The increase of meaning motion (AIM), the increase is improved with mesocarb rather than Te Suofenxin processing.As a result it is shown in Figure 2.Such as figure Shown in 2, the L-3,4 dihydroxyphenylalanine of the rat of mesocarb rather than Te Suofenxin improvement 6-OHDA processing induces property dyskinesia.
The increase for causing AIM is handled with L-3,4 dihydroxyphenylalanine, should by the mesocarb that rear 30min administrations are applied in L-3,4 dihydroxyphenylalanine Increase reduces about 40%.The effect is seen after L-3,4 dihydroxyphenylalanine is applied within 30 minutes and 60 minutes.Apply under the same conditions Te Suofenxin (a kind of non-specific catecholamine reuptaking inhibitor) is not acted on the AIM in the research.These data show Show, mesocarb can reduce L-3,4 dihydroxyphenylalanine induction property dyskinesia in PD preclinical models, and it is functionally different In non-specific DAT inhibitor such as Te Suofenxin.
Embodiment 3：The anti-akinetic enhancing of L-3,4 dihydroxyphenylalanine mediation
Damaged in 6-OHDA- in rat, also trigger the upper beneficial anti-motion for the treatment of can not be active using L-3,4 dihydroxyphenylalanine, the activity (FAS) test can be adjusted by forelimb step number to measure.In order to determine work(of the mesocarb to L-3,4 dihydroxyphenylalanine to the motor function The effect of effect, damage rat with the combined treatment 6-OHDA- of L-3,4 dihydroxyphenylalanine and 10mg/kg mesocarbs and tested by FAS Assessed (referring to Fig. 3).Compared to vehicle control, being handled two with L-3,4 dihydroxyphenylalanine causes motor function to increase.Using 10mg/ Kg mesocarbs cause significantly higher step number to adjust scoring with L-3,4 dihydroxyphenylalanine compared to vehicle control, and compared to independent L-3,4 dihydroxyphenylalanine increase scoring.
Forelimb step number regulation test implementation is as follows：
Disposal and training：
The continuous experimenter three, studied is disposed to rat, therefore they are familiar with the grasping of experimenter： Rat is retained as fixing hind leg with a hand and slightly rise rear portion is higher than surface；Another hand is fixed not monitored Forelimb；Forelimb to be monitored is set to contact desk；Animal is set slowly to be displaced sideways (about 5sec, 90cm), first in forehand side Carry out, then carried out on backhand direction upwards；And repeat these steps for another forelimb.Forehand is defined as towards body The compensation movement of body, and backhand is defined as the compensation away from body and moved.
Test
Each marching test is made up of 6 experiments of every fore paw, between forehand and backhand both direction alternately It is as follows：Rat is set to be maintained at same position as described above, a pawl contacts desk；Rat is set slowly to be displaced sideways (big About 5sec, 90cm), carry out on forehand direction, then carried out on backhand direction first；Two pawls are moved in forehand and backhand Step number regulation number on direction is counted and recorded；And testing sequence is that left claw forehand and backhand regulation stride, Zhi Houshi Right pawl backhand and forehand direction.Make rat be back to it to support cage and repeat the order with second rat in cage.To every Rat carries out 5 experiments again, puts back to rat in their foster cage between experiment.
Administration：
Tested with this part is carried out as follows within least 1 week after rotary test within 3-4 weeks after 6-OHDA infringements：Starting to be administered Before, trained rat and baseline executed as described above test；Prepare with benserazide L-3,4 dihydroxyphenylalanine (concentration is used for intraperitoneal injection, 10ml/kg)；A) L-3,4 dihydroxyphenylalanine is dissolved in salt solution with 1.2mg/ml；And b) benserazide is dissolved in salt solution with 0.4mg/ml；Prepare Mesocarb 10mg/kg (concentration is used for intraperitoneal injection, 10ml/kg)：A) mesocarb is dissolved in 0.5% with 1mg/ml Methylcellulose, 0.2% Tween 80 are (in dH2In O) in.
1st day
Weigh rat and injected with L-3,4 dihydroxyphenylalanine/benserazide (12mg/kg/4mg/kg).After L-3,4 dihydroxyphenylalanine/benserazide administration Carry out FAS within about 60 minutes.Rat is set to be back in foster cage.
2nd day
Weigh rat and before the administration of L-3,4 dihydroxyphenylalanine/benserazide 30 minutes with mesocarb 10mg/kg or medium ( dH20.5% methylcellulose, 0.2% Tween 80 in O) injection.Continue remaining research as described in the 1st day。
Data are expressed as by the step number (positive and backhand) of total impaired forelimb and by income value divided by complete forelimb Step number summation and the percentage that is multiplied by 100 and obtained, obtain that fore paw is disabled to be measured.Percentage to being damaged forelimb Similar calculating is obtained, obtains measuring for function gain.
As shown in Figure 3, check the evaluation that property motion effect is induced L-3,4 dihydroxyphenylalanine in the rat that is handled in 6-OHDA.As above Text is described with 6-OHDA Unilateral injection Sprague-Dawley rats (6/group).After two weeks, the amphetamine for testing rat lures Hair property rotary moveable with confirm dopaminergic damage.After extra one week, rat (the 1st day) is handled with 12mg/kg L-3,4 dihydroxyphenylalanine, Then with 10mg/kg L-3,4 dihydroxyphenylalanine and mesocarb processing rat (the 2nd day).Fore paw regulation step number is scored and incited somebody to action It is illustrated as the percentage of complete (unaffected) forelimb.Compared to medium (untreated), handled and produced with L-3,4 dihydroxyphenylalanine The small increase of step number.Compared to medium, 10mg/kg mesocarbs generation regulation step number dramatically increases (actual last time To 100%).(compared to veh+veh, * * p<0.01, p=0.058, carry out unidirectional ANOVA and (post-hoc) t- afterwards and examine Survey).These results establish that L-3,4 dihydroxyphenylalanine induces the rat model of property step number test and to show that mesocarb can strengthen L- more Bar exercise performance effect.In addition, mesocarb can allow the L-3,4 dihydroxyphenylalanine using lower therapeutic dose, thus reduce potential L-3,4 dihydroxyphenylalanine induce property side effect.
Embodiment 4：Mouse spacious field activity
Spacious field activity measure is carried out, wherein assessing kinematic parameter and sensorimotor parameter in spacious field device is automated. MPTP (MPTP) injection (3 × 20mg/ was carried out with 2 hours intervals in C57B1/6 mouse Kg) (MPTP final dose=60mg/kg).Mouse is handled with compound, and once a day, continues 4 within 30 minutes before MPTP Day.30 minutes after test compound is applied, monitor motor activity within 5th.Surveyed in automation spacious field (MedAssociates) Measure motor activity 30 minutes.Measure following parameter：1) horizontal range of traveling, 2) rears event (rearing event) Number and 3) stereotypic behavior.The result of Vertical movements (rears event) is shown in Figure 4.
Mesocarb and Te Suofenxin both of which prevent subtracting for the Vertical movements of the C57B1/6 mouse with MPTP processing It is few.These as shown by data mesocarbs can prevent toxicity MPTP intake, and this is consistent with DAT suppression mechanisms, and can be in PD Preclinical models in prevent symptomatic dyskinesia.
Embodiment 5：Mouse electroencephalogram
EEG data is obtained in the C57B1/6 mouse for be chronically implanted electrode to monitor brain and muscle activity. 4 hours after turning on light, when mouse is largely sleeping, the percentage of time used in waking up is assessed after intraperitoneal injection mesocarb Than.As a result it is shown in Figure 5.
As shown in Figure 5, wakeup time is dose-dependently increased compared to vehicle control, mesocarb.These As shown by data mesocarb can mitigate interruptions of sleep and the illness relevant with PD.
Embodiment 6：The reduction of L-3,4 dihydroxyphenylalanine induction property dyskinesia：Long term administration
Checked in the 6-OHDA rats for the unilateral lesions for handling 2 weeks with the L-3,4 dihydroxyphenylalanine with and without mesocarb pair benzene this Effect of the ketoamine to abnormal involuntary movement (AIM).
Drug-treated
Using 12mg/kg (ip) dosage level L-3,4 dihydroxyphenylalanine together with benserazide (ip；4mg/kg).Apply L-3,4 dihydroxyphenylalanine/ Apply mesocarb (10 or 30mg/kg, ip), amantadine (40mg/kg, ip) or medium within 30 minutes before benserazide.Make For " starting " step, after amphetamine rotates the elution phase, L-3,4 dihydroxyphenylalanine is individually applied 1 week once a day.Then, by double benzene This ketoamine is given extra 12 days once a day together with L-3,4 dihydroxyphenylalanine.
Abnormal involuntary movement (AIM)
By the way that based on Cenci et al., Nat.Rev.Neurosci., 2002, the method evaluation described in 3,574-9 is single The grade of the abnormal limbs of animal, oral area and facial movement assesses the long-term L-3,4 dihydroxyphenylalanine combined individually or with mesocarb Effect.After treatment, rat is placed in limitation room and following every 20-30 minutes monitors its axial direction, limbs and dispute AIM, continue 2 hours：
1. first minute, AIM is evaluated in three regions：
A. axially：The neck of bodyside and the dystonic posture of trunk of infringement offside are pointed in a manner of distorting；
B. forelimb：The quick no purpose motion of forelimb in the bodyside of infringement offside；With
C. dispute：When rat is not chewing or do not identifying food or other objects, the repeatability that jaw occurs often is opened Put and close and the stretching of tongue.
2. AIM is scored and recorded by 0 to 4 scale：
0=is not present；
1=is present in the observation period less than 50%；
2=is present in for 50% or more observation period；
3=is present in the whole observation period but interrupted by big Sound stimulat (knocking on cage)；With
4=is present in the whole observation period and not interrupted by big Sound stimulat.
3. second minute, calculating offside rotation, it is defined as complete 360 ° of rotations of the impaired side away from brain.
4. homonymy rotation is counted as negative and therefore deducted from total offside rotation.
5. for each AIM subcategories, add up to the scoring of whole test phase.
L-3,4 dihydroxyphenylalanine induction property dyskinesia is evaluated in the rat of 6-OHDA processing
Use 6-OHDA Unilateral injection Sprague-Dawley rats (10/group) as discussed previously.After two weeks, rat is tested Amphetamine induce property rotary moveable with confirm dopaminergic damage.After extra one week, measurement baseline AIM and use The mesocarb processing rat of 12mg/kg L-3,4 dihydroxyphenylalanine and 10mg/kg and 30mg/kg (ip) 12 days.The 1st day, the 8th Day, the 10th day and the 12nd day, AIM was scored in every 20 minutes, continue 2 hours, and be illustrated as axial direction, limbs and mouth The summation (Fig. 6) of tongue (ALO) abnormal motion.Compared to baseline, AIMS increase is produced with the L-3,4 dihydroxyphenylalanine processing of the dosage.Compare In medium, the reduction for producing AIM is handled with mesocarb.
Embodiment 7：The reduction of L-3,4 dihydroxyphenylalanine induction property dyskinesia：It is administered orally
The evaluation mesocarb Plasma Drug Level in Sprague-Dawley rats (3/group)
Via oral tube feed (po) with different times point of the 10mg/kg to rat using mesocarb and upon administration From blood plasma.In two kinds of different mediums (Tween-80 of 0.5% methylcellulose/0.2% and ethanol:Propane diols:Water (1:3: 1) mesocarb is prepared in).The comparison of both drug media things is carried out with true in pharmacokinetics (PK) research Whether the more preferable deliquescent preparation based on ethanol of fixed output quota life for the standard Cologel in previous research with having Similar property.By the levels of drugs of standard LC/MS technical Analysis plasma samples and it is reported as ng/ml.Two kinds of medicines Thing preparation generates similar PK curves, wherein producing slightly higher blood plasma level (figure in several time points based on the preparation of ethanol 7)。
Evaluation induces property dyskinesia via mesocarb is orally given in L-3,4 dihydroxyphenylalanine in the rat of 6-OHDA processing The effect of middle
Use 6-OHDA Unilateral injection Sprague-Dawley rats (10/group) as described herein.After two weeks, rat is tested Amphetamine induce property rotary moveable with confirm dopaminergic damage.After extra one week, measurement baseline AIM and use 12mg/kg L-3,4 dihydroxyphenylalanines and 10mg/kg and 30mg/kg (po) mesocarb processing rat 12 days.It is fine in 0.5% methyl Dimension element/0.2% compounding pharmaceutical in Tween-80.5th day and the 12nd day, AIM was scored in every 20 minutes, continue 2 hours, and And it is illustrated as the summation (Fig. 8) of axial direction, limbs and dispute (ALO) abnormal motion.It is more with the L- of the dosage compared to baseline Bar processing produce AIMS increase.Compared to medium, the reduction for producing AIM is handled with mesocarb via oral administration.
Embodiment 8：The anti-akinetic enhancing of L-3,4 dihydroxyphenylalanine mediation：Long term administration
Study using have mesocarb and without mesocarb L-3,4 dihydroxyphenylalanine handle 2 weeks unilateral lesions 6- In forelimb regulation step number (FAS) test of OHDA rats, effect of the mesocarb to motor function.
Drug-treated
Using the L-3,4 dihydroxyphenylalanine of 6mg/kg (ip) dosage level together with benserazide (ip；2mg/kg).Applying L-3,4 dihydroxyphenylalanine/benzyl silk Apply mesocarb (10 or 30mg/kg, ip) or medium within 30 minutes before hydrazine.As " starting " step, revolved in amphetamine After turning the elution phase, L-3,4 dihydroxyphenylalanine is individually applied 1 week once a day.Then, it is mesocarb is daily together with L-3,4 dihydroxyphenylalanine Once give extra 12 days.For these 6mg/kg L-3,4 dihydroxyphenylalanine research, two previous L-3,4 dihydroxyphenylalanines/bis- benzene this ketone will be come from The rat of amine research combines and allows the elution phase of 3 weeks.
L-3,4 dihydroxyphenylalanine induction property motion effect is evaluated in the rat of 6-OHDA processing
Use 6-OHDA Unilateral injection Sprague-Dawley rats (10/group) as described herein.After two weeks, rat is tested Amphetamine induce property rotary moveable with confirm dopaminergic damage.After extra one week, measurement baseline FAS and 6mg/ is used The mesocarb processing rat of kg L-3,4 dihydroxyphenylalanine and 3mg/kg and 10mg/kg (ip) 12 days.5th day and the 12nd day, per small Shi Yici is scored FAS, continues 3 hours, and it is illustrated as into impacted pawl % (Fig. 9) compared to baseline.Compared to Baseline, the small increase of regulation step number is produced with the L-3,4 dihydroxyphenylalanine processing of the dosage.Compared to medium, with this ketone of the double benzene of 3mg/kg Amine processing produces the increase of regulation step number.
Embodiment 9：The anti-akinetic enhancing of L-3,4 dihydroxyphenylalanine mediation：It is administered orally
By being checked in forelimb step number regulation (FAS) test of the 6-OHDA rats in the unilateral lesions handled with L-3,4 dihydroxyphenylalanine Mesocarb determines the ability of mesocarb generation Orally active to the effect of motor function.
Drug-treated
Using the L-3,4 dihydroxyphenylalanine of 6mg/kg (ip) dosage level together with benserazide (ip；2mg/kg).Applying L-3,4 dihydroxyphenylalanine/benzyl silk Apply mesocarb (10mg/kg, po) or medium within 30 minutes before hydrazine.As " starting " step, washed in amphetamine rotation After failing to come out on time, L-3,4 dihydroxyphenylalanine is individually applied 1 week once a day.Then, by mesocarb together with L-3,4 dihydroxyphenylalanine once a day Give extra 12 days.
L-3,4 dihydroxyphenylalanine induction property motion effect is evaluated in the rat of 6-OHDA processing
Use 6-OHDA Unilateral injection Sprague-Dawley rats (3/group) as described herein.After two weeks, rat is tested Amphetamine induce property rotary moveable with confirm dopaminergic damage.After extra one week, measurement baseline FAS and 6mg/ is used The mesocarb processing rat of kg L-3,4 dihydroxyphenylalanine and 10mg/kg (po) 12 days.12nd, 60 minutes to FAS upon administration Scored, and it is illustrated as impacted pawl % (Figure 10) compared to baseline.Compared to medium (single L-3,4 dihydroxyphenylalanine), The small increase for generating regulation step number is orally administered with 10mg/kg mesocarbs, and is important to not reduce.
Embodiment 10：Individually handled in the rat of 6-OHDA- infringements with mesocarb and do not cause motion or function Defect
Mesocarb is studied in the 6-OHDA rats of the unilateral lesions of unused L-3,4 dihydroxyphenylalanine processing to abnormal nonvoluntary fortune The effect of dynamic (AIM).
Drug-treated
3mg/kg (ip) mesocarb is applied to 6-OHDA- infringement rats once a day, continues 12.
Dyskinesia after assessment is handled with mesocarb in 6-OHDA infringement rats
Use 6-OHDA Unilateral injection Sprague-Dawley rats (3/group) as described herein.After two weeks, rat is tested Amphetamine induce property rotary moveable with confirm dopaminergic damage.After extra 6 weeks, measurement baseline AIM and 3mg/ is used Kg (ip) mesocarbs handle rat 12.Do not apply L-3,4 dihydroxyphenylalanine in this experiment.5th day and the 12nd day, upon administration 30 minutes, 90 minutes and 150 minutes axial directions of being scored AIM and be illustrated as, limbs and dispute (ALO) abnormal motion Summation (Figure 11).Handled with single mesocarb and produce nominal AIM, scoring is about 1/20 handled with L-3,4 dihydroxyphenylalanine.
The scope of the present disclosure is not limited to the explanation for being intended to some aspects as the disclosure disclosed in embodiment Specific embodiment, and functionally equivalent any embodiment is in the scope of the present disclosure.In fact, to the disclosure Will become obvious to those skilled in the art except a variety of modifications of those shown and described herein and It is intended to fall within the appended claims.
Many bibliography are quoted, the entire disclosure is incorporated herein by reference.

Claims (13)

1. the mesocarb of effective dose or its pharmaceutically acceptable salt are preparing the levodopa for treating people Purposes in the medicine of dyskinesia.
2. purposes as claimed in claim 1, wherein the administration of the medicine is oral.
3. purposes as claimed in claim 1, wherein the mesocarb or its pharmaceutically acceptable salt are present in medicine In composition.
4. purposes as claimed in claim 3, wherein described pharmaceutical composition are tablet, pill or capsule form.
5. purposes as claimed in claim 3, wherein the application dosage of the mesocarb is per 0.01 milligram of kg body weight To 70 milligrams.
6. purposes as claimed in claim 3, wherein the application dosage of the mesocarb be per 0.1 milligram of kg body weight extremely 50 milligrams.
7. purposes as claimed in claim 3, wherein the application dosage of the mesocarb be per 0.5 milligram of kg body weight extremely 20 milligrams.
8. purposes as claimed in claim 3, wherein described pharmaceutical composition also include another therapeutic agent.
9. purposes as claimed in claim 8, wherein another therapeutic agent is L-3,4 dihydroxyphenylalanine.
10. purposes as claimed in claim 1, wherein the levodopa dyskinesia is aperiodicity tension force barrier Hinder, Bipolar dyskinesia or peak dose dyskinesias.
11. compound or its pharmaceutically acceptable salt including following formula are preparing the levodopa fortune for treating people Purposes in the medicine of dynamic obstacle：
Wherein：U is C；W is H；Y is H；X is O；Z is O；Q is phenyl；R1It is 1 for H and r；R2And R3It is 1 for H and n；R4And R5For H And p is 1；R7For H；And R8For H.
12. purposes of the pharmaceutical composition in the medicine for preparing the levodopa dyskinesia for being used for treating people, described Composition is tablet, pill or capsule form, and includes the chemical combination for including following formula of every 0.01 milligram to 70 milligrams of kg body weight Thing：
Or its pharmaceutically acceptable salt, wherein：U is C；W is H；Y is H；X is O；Z is O；Q is phenyl；R1It is 1 for H and r；R2 And R3It is 1 for H and n；R4And R5It is 1 for H and p；R7For H；And R8For H.
13. purposes as claimed in claim 12, wherein described pharmaceutical composition further comprise L-3,4 dihydroxyphenylalanine.
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